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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pathogen resistance'. | Intravesical acetic acid in combination with prophylactic methenamine and ascorbic acid to decrease the incidence of recurrent urinary tract infections associated with intermittent urinary self-catherization: A case report.
A case is presented demonstrating improved efficacy of the use of oral methenamine hippurate and vitamin C urinary tract infection prophylaxis achieved by adding self-administered acetic acid irrigation twice daily during routine intermittent bladder self-catheterization in a post-menopausal female patient with multiple sclerosis. The patient in this case report is me, a retired radiologist.
Introduction
Recurrent urinary tract infection in susceptible patient populations is difficult to treat over the long term. It is common in patients who perform intermittent urinary self-catheterization, where intracystic inoculation of bacteria is difficult to avoid.
Most commonly isolated urinary pathogens in a cohort of patients studied1 is Escherichia coli, followed by Klebsiella, Staphylococcus aureus, Pseudomonas, Serratia, Enterobacter and Streptococcus. The more resistant bacterial strains were found to be sensitive to intravenous antibiotics only. In that study, two strains of E.coli and one of Klebsiella were found to be resistant to all antibiotics tested, and treatment of infection in these patients was a therapeutic dilemma.
As recurrent UTIs require suppressive therapy to improve quality of life and minimize complications including pyelonephritis, renal impairment and sepsis, low-dose antibiotic prophylaxis has been a mainstay.
Oral administration of methenamine salts has been found to be useful for prevention of UTIs by sterilizing the urine without the use of antibiotics2 to avoid selection of antibiotic-resistant infection. When excreted in an acidic urine formaldehyde is formed. The recommended dose is 1 gm methenamine hippurate po bid. Although oral methenamine alone results in some urinary acidification, ascorbic acid 1 gm po bid is added for augmentation.
Patient information
The patient is a 68 year old, post-menopausal woman with a 20 year history of multiple sclerosis. Fifteen years ago the patient began practicing intermittent bladder self-catheterization because of urinary retention. Symptomatic bladder infections occurred bimonthly with pyuria and >100,000 colonies of bacteria per HPF in catheter specimens.
Prophylactic low-dose daily nitrofurantoin was initially successful, but after several months became ineffective with pan-sensitive E. coli and Klebsiella infections.
Prophylaxis with low dose oral trimethoprim/sulfamethoxazole was initiated which failed after several months with resistant E. coli species. This was followed by cephalexin suppression, which failed after several months resulting in pyelonephritis, with dysuria, back pain, fever and leukocytosis. Urine culture revealed pan-resistant, ESBL E.coli, requiring hospital admission and intravenous ertapenum.
UTI suppression with ciprofloxacin and cephuroxime was then attempted, again with only brief success resulting in pan-resistant bacterial infections.
After five years of unsuccessful antibiotic prophylaxis, bladder irrigation with antibiotics3, 4 was considered, however not elected. Instead, 1 g of oral methenamine hippurate bid accompanied by 1 g of vitamin C for urine acidification was prescribed resulting in the best outcome to date, with bacterial cystitis every 4–5 months sensitive to oral antibiotics. The patient checked urine pH regularly which was acidic at 6.0–6.5, likely explaining the increased success, although urinary pH no higher than 5.5 is optimal for formaldehyde production. The patient sought a more dependable approach to urinary acidification to further decrease infection.
Daily bladder irrigation with acetic acid was investigated
Bladder irrigation with a 0.25% solution of white vinegar is suggested for children on intermittent catheterization with chronic bacteriuria and/or stones.5 Although vinegar irrigation alone appears to decrease bacteriuria, this patient suspected that irrigating with vinegar was likely to lower the intravesicular pH, which could enhance successful formation of formaldehyde from methenamine hippurate. She therefore developed a technique for home use.
Therapeutic intervention
A “clean” technique as used for standard intermittent bladder catheterization was chosen. It was designed to be simple for home use, and performed twice a day, at bedtime and upon rising.
Materials
Coloplast, 14 gauge sterile hydrophilic disposable urinary catheter
Benzalkonium antiseptic wipes for pre-catheterization perineal cleansing
BD 60 cc sterile catheter-tip syringe
Sterile 4 ounce specimen cup
2 × 2 sterile gauze pad
5% white table vinegar in quart bottle: one capful measured 5 cc
Approximately 90–100 cc of warm tap water in cup (slightly over 3 oz)
Procedure
1. Wash hands.
2. Pour one capful (5 cc) of white vinegar (5%) into the specimen cup and dilute with just over 3 ounces (90–100 cc) of warm tap water, resulting in an approximately 0.25% vinegar solution.
3. Fill 60 cc syringe with the solution, and pre-lubricate catheter with tap water.
4. Cleanse perineum with BZK wipes, insert water-lubricated catheter, and drain urine
5. Attach syringe filled with dilute vinegar to catheter and inject into bladder
6. Hold fluid in bladder for 30 seconds, then drain through catheter into bowl
7. Remove catheter
A new disposable catheter is used each time. The syringe and the cup are rinsed with hot water. A sterile gauze is placed in the cup and the syringe returned to packaging. The rinsed cup and syringe are re-used, and replaced twice a week.
Occasional testing of urine prior to irrigation assured maintenance of an acidic pH of 5.5.
Results
The patient was free of urinary-tract infection for 8 months, after which a pan-sensitive E. coli infection was treated satisfactorily with oral antibiotics. She continued vinegar irrigation and maintained urinary acidity. Over the following 6 years she was largely infection-free, having two additional culture-positive infections with pan-sensitive E.coli. There were neither infections with resistant organisms nor clinical evidence of upper tract infection.
Conclusion
While taking oral methenamine for UTI prophylaxis in a patient performing intermittent bladder self-catheterization, routine vinegar bladder irrigation appeared to dramatically reduced the incidence of infection. When infections did occur, they were caused by organisms without significant resistance profiles. Given my history of potentially life-threatening infections, I believe this technique merits further evaluation for patients performing intermittent bladder self-catheterization.
Discussion
It has been shown that bladder irrigation with 0.25% vinegar decreases bacteriuria, which alone can reduce infection. Results here suggest a greater effect than would be expected with irrigation alone, felt likely due to the increased production of formaldehyde in the urine with oral methenamine salts.
Studies comparing the two modalities and prospective analysis of formaldehyde concentration in the urine could be helpful, as would evaluation of the apparent change of infecting flora from resistant strains to pansensitive organisms.
Note
This case report represents findings in a single patient. Discussions of bladder irrigation with acetic acid5 recommend the use of sterile saline rather than the tap water used in this case. Assessment of safety of this technique should be determined for the individual patient in consultation with a physician. | CIPROFLOXACIN | DrugsGivenReaction | CC BY-NC-ND | 33365254 | 18,729,213 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal haemorrhage'. | Gastrointestinal Bleeding Rates in Left Ventricular Assist Device Population Reduced with Octreotide Utilization.
Patients with continuous-flow left ventricular assist devices have a high risk of gastrointestinal bleeding (GIB) and recurrent bleeding. Studies have shown octreotide can reduce the risk of GIB. This retrospective, case-crossover study, evaluated the efficacy of octreotide for the prevention of recurrent GIB in patients with left ventricular assist devices between August 2008 and October 2018. A total of 32 patients received octreotide and were included in the study. Hospital admission for GIB was evaluated before and after the initiation of octreotide. Each case served as his/her own control. Most patients were on a reduced aspirin dose (56.2%) and had a reduced international normalized ratio goal (59.4%) before starting monthly octreotide. The most common dose of long-acting octreotide was 30 mg every 28 days. Overall, octreotide decreased the frequency of GIB (4.3 vs. 0.9 events/year, p < 0.001). Nineteen (59.4%) patients did not have a subsequent gastrointestinal bleed. Of the 13 patients who rebled after initiation of octreotide, the frequency of events decreased by 2.6 bleeds per patient per year (4.8 vs. 2.2; p = 0.043). In high-risk patients who have failed conventional therapy, octreotide can be useful for the prevention of recurrent GIB.
Gastrointestinal bleeding (GIB) is one of the most common complications in patients on continuous-flow left ventricular assist device (CF-LVAD) support and is associated with increased morbidity and mortality.1 The incidence of GIB after implantation of a CF-LVAD ranges between 15.4% and 61.0%.2,3
The pathophysiology of GIB in patients with CF-LVADs is multifactorial. The risk factors for increased likelihood of GIB in patients with CF-LVADs include chronic anticoagulation, antiplatelet agents, device physiology causing high shear stress resulting in acquired Von Willebrand disease, impaired platelet aggregation, formation of arteriovenous malformations, angiodysplastic lesions, and intestinal hypoperfusion.2–6 Various interventions to reduce the incidence of GIB include reduced antiplatelet dose, lower target international normalized ratio (INR) goals, decreased pump speed to allow for aortic valve opening, use of proton pump inhibitors or histamine-2 receptor antagonists, treatment with thalidomide, danazole, or octreotide.1,7–10
Octreotide is a somatostatin analog, FDA approved for acromegaly, diarrhea associated with carcinoid tumors and vasoactive intestinal peptide (VIP) secreting neurogenic tumors. Octreotide is used off-label for treatment and secondary prevention of GIB. A few observational studies have shown a benefit with the use of long-acting release octreotide (LAR) for the prevention of recurrent GIB (Table 1).11–14 The largest of the studies included 51 patients with a 180 day follow-up in comparison to a historical cohort.12
Table 1. Key Studies Utilizing LAR in CF-LVAD Patients
Devices Number of Patients Octreotide Regimen Outcomes
Juricek et al.11 HMII 30 IM LAR depot 20 mg every 4 weeks Decreased frequency of GIB 3.4 ± 3.1 to 0.7 ± 1.3 events/year; p < 0.001
HVAD Heartassist
Shah et al.12 HMII 51 IM LAR depot (37) or SQ daily (14) for 6 months Increased freedom from rebleeding GIB for the octreotide group, 75 ± 6% vs 52 ± 8%, p < 0.01
Malhotra et al.13 HMII 8 IM LAR depot 20 mg every 4 weeks for 16 weeks No episodes of GIB observed or reported
Smallfield et al.14 Devices not specified 34 IM LAR depot monthly or SQ daily (doses not specified) IM LAR depot monthly had lower rate of bleeding compared to SQ daily (29% vs. 42%)
CF-LVAD, continuous-flow left ventricular assist device; GIB, gastrointestinal bleed; HMII, HeartMate II; HVAD, HeartWare HVAD System; LAR, long-acting release.
We conducted a retrospective cohort study evaluating the use of LAR at a single center over a 10 year period examining the incidence of GIB prior and following LAR therapy.
Materials and Methods
Patient Population
A retrospective, crossover study was conducted at Sentara Norfolk General Hospital. The study inclusion criteria included patients aged 18 years and older, CF-LVAD placement from August 2008 to October 2018, a GIB requiring hospital admission, standard-of-care treatment for secondary prophylaxis, and treatment with monthly LAR. Patients were excluded if they missed greater than two consecutive doses of LAR (Table 2). The study was approved by the Eastern Virginia Medical School Institutional Review Board.
Endpoints
Each patient served as their own control to compare GIB rates. The control period was time from CF-LVAD implant to initiation of LAR (pre-LAR), whereas the comparison period was time from the initiation of LAR (post-LAR) until the end of follow-up. The primary endpoint was bleeding events per patient per year pre-LAR in comparison with post-LAR. A bleeding event was defined as a GIB resulting in hospitalization. Although subject to clinical assessment, patients were generally admitted to the hospital for a decrease of 2 g/dl of hemoglobin or signs of a GIB, such as a positive fecal occult blood sample. After evidence of GIB, colonoscopies, and endoscopies were routinely performed. If no bleeding source was identified, additional invasive procedures such as spiral enteroscopy would be performed.
Institution-Specific Protocols
Patients on CF-LVAD support were initially placed on aspirin 325 mg daily, warfarin with a goal INR of 2–3, and a proton pump inhibitor or histamine-2 receptor antagonist. Regimens after first bleed were then individualized per patient. Modifications to the INR goal, antiplatelet regimen, pump speed, or initiation of octreotide were considered before discharge at the discretion of the attending cardiologist. Per protocol, patients initiate octreotide when modifiable causes for bleeding (e.g., supratherapeutic INR or a lesion requiring cauterization) have been fixed. Patients started on octreotide continue monthly or more frequently until transplant or the patient expires.
Statistical Analysis
Paired categorical data were evaluated using the McNemar’s test. For continuous data, the paired t-test or Wilcoxon signed-rank test was utilized. We then performed a mixed effects analysis of variance (ANOVA) model and included a random effect for patient ID to account for correlation between pre and post measurements within the same patient. In this three-way full factorial ANOVA, we evaluated the impact of octreotide, a reduced INR goal, and reduced aspirin dose on the outcome of GIB frequency. A Kaplan–Meier analysis with a log rank test was utilized to determine the impact of LAR on the freedom from rebleeding. Statistical analysis was completed with IBM SPSS statistics software version 24.
Results
Thirty-four patients out of 321 CF-LVAD implants during the study period developed a GIB and were initiated on LAR. Two of these patients were excluded, one due to receiving LAR for epistaxis and another due to missing greater than two consecutive doses of LAR. Pharmacokinetically when three consecutive doses are missed (3 months), the intramuscular drug is completely eliminated from the body. A total of 32 patients were included in the analysis, 15 (46.9%) had HeartMate II (Abbott, IL), 13 (40.7%) HVAD (Medtronic, MN), and 4 (12.4%) HeartMate III (Abbott, IL) (Figure 1).
Figure 1. Patient selection.
Baseline characteristics of the patients at the time of admission before the initiation of LAR are shown in Table 2. As this was a refractory patient population, most pre-LAR patients were on a reduced dose aspirin (56.2%), lower INR goal (59.4%), and were on a proton pump inhibitor (93.8%).
Table 2. Patient Characteristics
Patient Demographics
Gender: male, n (%) 25 (78.1)
Age at LVAD implantation, mean ± SE 61.2 ± 1.2
Body mass index, mean ± SE 30.4 ± 0.91
Race, n (%)
Caucasian 16 (50.0)
African American 16 (50.0)
Past medical history, n (%)
Hypertension 26 (81.3)
Ischemic etiology 23 (71.9)
Atrial fibrillation 21 (65.6)
History of ventricular tachycardia 21 (65.6)
Diabetes mellitus 18 (56.3)
History of prior bleeding events 13 (40.6)
History of prior thrombotic events 9 (28.1)
Current infection 3 (9.4)
LVAD, n (%)
Heartmate II 15 (46.9)
HVAD 13 (40.7)
Heartmate III 4 (12.4)
CF-LVAD rotations per minute, mean ± SE
Heartmate II 9,211.3 ± 105.9
HVAD 2,821.5 ± 61.0
Heartmate III 5,550.0 ± 236.3
Destination therapy, n (%) 17 (53.1)
INR at the time of the bleed before LAR, mean ± SE 2.2 ± 0.094
Aspirin, n (%)
None 8 (25.0)
81 mg 9 (28.1)
162 mg 1 (3.1)
325 mg 14 (43.8)
Angiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist use, n (%) 19 (59.4)
Digoxin use, n (%) 4 (12.5)
Acid suppression therapy, n (%)
Proton pump inhibitor 30 (93.8)
Histamine-2 receptor antagonist 2 (6.2)
CF-LVAD, continuous-flow left ventricular assist device; HMII; HVAD; LAR, long-acting release.
All patients had a therapeutic INR at the time of GIB before LAR initiation. Characteristics related to GIB events and their management can be found in Table 3. Post-LAR there were more patients on a reduced aspirin dose (p = 0.04) and lower INR goal (p = 0.02). There was no difference between patient follow-up time pre-LAR and post-LAR (393.5 vs. 470.3 days, p = 0.4).
Table 3. Patient Management Parameters Pre-LAR and Post-LAR
Interventions Pre-LAR Post-LAR p
Recurrent bleeding management
Reduced aspirin dose (<325 mg), n (%) 18 (56.2) 25 (78.1) 0.04
Aspirin, n (%)
None 8 (25.0) 18 (56.2) 0.04
81 mg 9 (28.1) 7 (21.9)
162 mg 1 (3.1) 0 (0)
325 mg 14 (43.8) 7 (21.9)
Reduced INR goal (INR range 2–3), n (%) 19 (59.4) 26 (81.3) 0.02
Dose of LAR (mg), median, [interquartiles] 30.0 [20.0–40.0]
Dose frequency of LAR (days), median, [interquartiles] 28 [21–28]
Angiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist use, n (%) 19 (59.4) 15 (46.9) 0.22
Digoxin use, n (%) 4 (12.5) 5 (15.6) 1.00
CF-LVAD support parameters and durations
Reduced CF-LVAD rotations per minute, n (%) 3 (9.4)
Patient follow-up (days), mean ± SE 393.5 ± 73.6 470.3 ± 57.8 0.4
Outcome measures
Patients with recurrent GIB, n (%) 32 (100) 13 (41) <0.01
Number of GIB median, [interquartiles] 2.0 [1–3] 0 [0–1] <0.01
Frequency of GIB per year, median, [interquartiles] 2.95 [1.2–5.7] 0 [0–1.4] <0.001
CF-LVAD, continuous-flow left ventricular assist device; GIB, gastrointestinal bleed; INR, international normalized ratio; LAR, long-acting release.
Before the initiation of LAR, patients had an average of 4.3 ± 3.8 GIB events per year (median 2.0 GIB events per year), whereas post-LAR patients had an average of 0.9 ± 1.4 GIB events per year (median 0 GIB events per year). Our study showed that LAR significantly reduced the frequency of GIB events per year, p <0.001 (Figure 2). Most patients (87.5%, 28/32) had a positive response to LAR with a decrease in admissions for GIB. After initiating LAR, 59.4% (19/32) did not have a subsequent GIB. Of the 13 patients that bled after the initiation of LAR, the frequency of events decreased by 2.6 bleeds per patient per year compared with pre-LAR (2.2 vs. 4.8; p = 0.043).
Figure 2. Frequency of GIB pre-LAR and post-LAR. GIB, gastrointestinal bleed; INR, international normalized ratio.
Among the three devices studied, there was no difference in GIB frequency (p = 0.54) or effect of LAR (p = 0.28). A multivariate, mixed modeling analysis demonstrated that LAR significantly reduced GIB frequency (p < 0.01), whereas a reduced INR goal and reduced aspirin dose had no effect (p= 0.85, p = 0.54) (Tables 4 and 5). The Kaplan–Meier curves showed the time to first GIB for both pre-LAR and post-LAR. The 90 day freedom from GIB in pre-LAR was 50%, whereas in the same time frame, the post-LAR had 78% freedom from GIB (Figure 3).
Table 4. Overall F-Tests From the Mixed Modeling Full Factorial ANOVA
Variable F Sig
Intercept 42.0 1
Octreotide 24.47 <0.01
INR reduction (yes/no) 0.04 0.85
Aspirin reduction (yes/no) 0.39 0.54
INR × aspirin 0.07 0.79
Octreotide × INR 1.77 0.20
Octreotide × aspirin 0.02 0.89
Octreotide × INR × aspirin 0.01 0.93
INR, international normalized ratio.
Table 5. Estimated Magnitude of Main Effects
Variable Estimate 95% CI p
Octreotide −0.31 −0.43 to −0.18 <0.01*
INR reduction (yes/no) −0.014 −0.16 to 0.14 0.85
Aspirin reduction (yes/no) −0.046 −0.20 to 0.10 0.54
INR, international normalized ratio.
Figure 3. Kaplan–Meier graph displaying freedom from GIB. GIB, gastrointestinal bleed.
Of the 32 patients included in this study, two patients developed a pump thrombosis. Patient 1 had a HeartMate II that had been on LAR for 4 months, had an INR of 1.7 (INR goal 1.5–2.0) and was on aspirin 325 mg daily at the time of admission. Patient 2 had a HeartMate II that had been on LAR over 2 years, had an INR of 3.20 (INR goal 2.0–3.0), and on aspirin 81 mg daily at the time of admission. Both patients had a reduction in their anticoagulant or antiplatelet, making it difficult to ascertain the cause of the pump thrombosis.
Discussion
Despite improvements with CF-LVADs, GIB continues to be a vexing problem. This retrospective, case-crossover study aimed to evaluate the efficacy of LAR for prevention of recurrent GIB. Mehra et al.17 found that the incidence of GIB to be 0.31 and 0.49 GIB events per patient per year in HeartMate II and HeartMate III devices, respectfully. Our patients had a higher incidence of 4.3 ± 3.8 GIB events per patient per year. When analyzing the study’s incidence of GIB, we could consider that our patient population is higher risk for GIB compared with the average patient population. In our study, LAR prevented recurrent GIB in 59.4% of patients and showed an overall reduction of GIB in 87.5% of patients. Upon a multivariate analysis, only LAR significantly reduced the frequency of GIB, while reduced INR goal and reduced aspirin dose had no effect.
Previous studies have demonstrated the efficacy and safety of octreotide for recurrent GIB. Shah et al.12 used a historical cohort from the original HeartMate II trials and found that the use of octreotide in HeartMate II patients with or without prior GIB more than a 6 month period resulted in significantly fewer recurrent GIB (24% vs. 43%, p = 0.04) and increased freedom from rebleed (75% vs 52 ± 8%, p < 0.01). Our study mirrored these results at 6 months with fewer recurrent GIB (31% vs. 63%) and increased freedom from rebleed (67% vs. 38%). While on LAR, 13 patients had recurrent GIB and the majority of bleeds (10/13) occurred in the first 6 months. Despite this rebleeding, LAR decreased the frequency of GIB. Four patients did not respond to LAR and continued to have GIB.
Another study by Juricek et al.11 determined monthly LAR used in patients with HeartMate II, HVAD, and Heartassist CF-LVADs significantly reduced the frequency of GIB (3.0 ± 2.4 vs. 0.7 ± 1.3 GIB events/year, p < 0.05). Our study confirms these results with a similar decrease in GIB events/year (4.3 ± 3.8 vs. 0.9 ± 1.4, p < 0.001). Additionally, our study further elaborates on previous results evaluating outcomes with HeartMate III, continuing LAR longer than 12 months, and the impacts of adding LAR, adjusting aspirin dose, and INR goal on GIB. The use of octreotide resulted in reduction of GIB frequency and prevention of refractory GIB in patients with CF-LVADs.
Octreotide is known to be associated with adverse effects such as hyperglycemia, bradycardia, hypertension, diarrhea, and injection site reactions. None of the patients in this study had side effects that were attributed to octreotide. Cost is another factor in the decision-making process as an average dose of octreotide of 20 mg is $5,117.69 USD per month, limiting use to patients with insurance coverage. At this time, most insurance plans that serve the patients around our center in the United States appear to cover LAR, although prior authorizations may take up to 14 days delaying initiation of therapy. The use of octreotide decreased frequency of hospitalization for GIB in 87.5% of patients. The costs of LAR may be offset with reduced hospitalizations and could be appropriate in patients with multiple admissions for GIB.
Modifications to patient regimens such as reduction in aspirin dose, reduction in goal INR, and changes in CF-LVAD settings have been utilized in an attempt to reduce the frequency of GIB; however, these treatments may increase the risk for thrombotic events.15,16 Use of octreotide in this population may decrease readmissions rates and increase days spent out of the hospital.11 There are several inherent limitations in this study. This was a retrospective single-center and relatively small study, including 32 patients that received LAR at our center. On average, these patients had at least 2 GIB before initiation of octreotide when adjustments in aspirin dose and target INR failed to prevent recurrent GIB. This leads to a selection bias, identifying only patients with the most frequent GIB who failed conventional therapies. Another limitation would include simultaneous medication interventions such as reduced aspirin doses or INR goals, which confounds the impact of LAR on our results. There were additional gastrointestinal interventions concurrently performed on these patients when a source of bleeding was found that could also impact the results. Additionally, the changes in clinical practice over the long study time frame cannot be taken into account. Our results should be considered in the context of the refractory population studied. Efforts were taken to identify and eliminate confounders to prevent impact on results.
Conclusion
Overall, our study demonstrates that LAR is associated with a significant decrease in the frequency of GIB in high-risk patients with CF-LVADs. This study adds to prior literature and adds insight with additional follow-up time and the inclusion of the Heartmate III. Future prospective studies, including a randomized controlled trial, are needed to validate these findings.
Acknowledgment
Dr. Trent Gaugler, PhD, Associate Professor of Mathematics at Lafayette University.
Disclosure: Dr. Baran has consulting income from Abiomed, Getinge, Livanova, MC3, and speaking honoraria from Novartis and Pfizer. Dr. Herre has consulting income from LifeNet Health and receives grant support from Analytics 4 Life, Boston Scientific and DCRI. Dr. Yehya has speaking honoraria from Akcea therapeutics, CareDx, and Zoll. The other authors have no conflicts of interest to report. | ASPIRIN | DrugsGivenReaction | CC BY-NC-ND | 33369929 | 18,821,415 | 2021-09-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Berlin Excor Cannulation of Left Atrial Appendage in Left Ventricular Restrictive Physiology: A Novel Bailout Strategy.
Ventricular assist device (VAD) management continues to be a challenge in the presence of restrictive physiology. Left atrial (LA) decompression is not satisfactory even with good function and position of the left ventricular cannula. We describe an alternate approach with LA cannulation via the left atrial appendage (LAA) as a rescue strategy in a patient who had restrictive physiology, in our case was secondary to viral myocarditis acute systolic heart failure with subsequent insidious diffuse endomyocardial fibrosis and superimposed massive calcification, causing inadequate emptying of the left ventricle despite optimal VAD apical cannula position.
Extracorporeal ventricular assist device (VAD) support is commonly used in young children with severe heart failure to support them to recovery or heart transplant as the children are too small to be supported with adult-type intracorporal VADs. Some pediatric centers prefer the centrimag/pedimag for short-term support given more experience with this device. However, the Berlin Heart Excor has become the preferred VAD in other centers for children who require medium to long-term VAD. As worldwide experience with this type of VAD has expanded, there have been improved outcomes1 likely related to changes in the anticoagulation management, patient selection, a better understanding of VAD management, and also attributed to increased surgical experience with the implant techniques which improves hemodynamics.
VAD management continues to be a challenge in the presence of restrictive physiology. Left atrial decompression is not satisfactory even with good function and position of the left ventricular cannula. To combat this problem, techniques have been developed to cannulate the left atrium (LA) directly, particularly in hypertrophied ventricles or when the size of the ventricle would not allow for the appropriate position of the inflow cannula.2 The surgical technique of LA cannulation has been described previously,3 and typically involves cannulation of the rightward aspect of the LA directly or via the right pulmonary vein.
Herein, we describe an alternate approach with LA cannulation via the left atrial appendage (LAA) as a rescue strategy in a patient who had restrictive physiology secondary to viral myocarditis acute systolic heart failure with subsequent insidious diffuse endomyocardial fibrosis and superimposed massive calcification, causing inadequate decompression of the left ventricle (LV) despite optimal VAD apical cannula position.
CASE REPORT
A 6-year-old, 17 kg female presented to the emergency department with fever, tachycardia, and respiratory distress. Echocardiogram revealed a severely depressed bi-ventricular function. She rapidly decompensated with the development of acute cardiorespiratory failure and required intubation, and initiation of inotropic support with dopamine and epinephrine. Progression with acute pulmonary edema and ongoing severe cardiac failure refractory to maximal medical therapy required advanced mechanical support with peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) from femoral vessels approximately 12 hours after presentation. Because of left atrial distention on echocardiography, the patient was taken to cardiac catheterization for atrial septostomy. Her medical/surgical history was significant for renal transplantation at 2 years of age secondary to congenital renal dysplasia. Her post-renal transplant course was complicated by chronic graft dysfunction secondary to recurrent antibody-mediated rejection, Epstein Barr Virus (EBV) viremia, and post-transplant lymphoproliferative disorder.
Further evaluation of her decompensation revealed most likely enteroviral myocarditis (serum PCR positive for enterovirus). On VA-ECMO, the flows were ranging from 2 to 2.5 L/minute (LPM); however, despite the atrial septostomy the patient developed pulmonary hemorrhage and echocardiography showed evidence of ongoing severe left atrial hypertension with NT-pro B-type natriuretic peptide (BNP) 91.388 pg/mL and troponin peak 151.966 µg/ml. Therefore, the patient was transitioned 10 days later from peripheral VA-ECMO to a Thoratec CentriMag (Abbott) Bi-VAD support with cannulation of the right atrium (RA)/pulmonary artery (PA) for the right VAD and the left atrium(LA)/Ascending Aorta (Ao) for the left VAD (LVAD). With this cannulation strategy, the patient was well supported with excellent oxygenation, renal function, and adequate bi-VAD flows ranging from 2 to 2.5 LPM on the LVAD and 1.5 to 2.3 LPM on the RVAD. Conversion to longer-term mechanical support was needed 2 weeks later due to lack of myocardial recovery with ongoing systolic heart failure with left ventricular ejection fraction <20% preoperative head computed tomography (CT) scan showed subacute right middle cerebral artery stroke and foci of acute intraparenchymal hemorrhage within right frontal and parietal lobes. These findings were stable on repeat head CT 1 week later, and so the decision was made to proceed with Berlin Heart Excor (Berlin Heart Inc, The Woodlands, Tx) implant. After discussion with the technical support of Berlin Heart, we opted for a 25-mL Berlin Heart Excor Bi-VAD support, via 9 mm RA and left ventricular apical cannulae, and 6 mm pulmonary artery and ascending aortic cannulae. The settings on the Berlin Heart were adjusted to maintain optimal filling and emptying of both RVAD and LVAD, with initial settings with LVAD rate: 90 BPM, systolic pressure 210, diastolic pressure −40, and 35% systole, with RVAD Rate: 87 BPM, systolic pressure 175, diastolic pressure −25 and 35% systole.
Despite initial optimal filling and emptying of both VADs, in the following days, we encountered persistent difficulty with the filling of the LVAD with worsening pulmonary edema. This inadequate filling was not responsive to any adjustments of the Berlin settings in terms of diastolic pressure, rate of the device, and synchrony between the two VADs. Furthermore, the native heart was relatively bradycardic (maximum 80 beats/minute), which notoriously is a favorable factor for Berlin LVAD mechanics. The inadequate filling was thought to be secondary to restrictive physiology from the development of diffuse endomyocardial fibrosis and massive calcifications in the left ventricle (LV) myocardium (Figure 1). Because of this, the plan was to take the patient back to the operating room to change the left side inflow cannulation from the left ventricular apex to the LA. This was accomplished with the addition of a LA cannula through the LAA and using a Y-connection with the left ventricular apical cannula to a CentriMag continuous flow pump in exchange for the Berlin left-sided pump. The RVAD was also changed to a Centrimag pump at this time. The reason this unusual configuration was adopted was to avoid another run of cardiopulmonary bypass (CPB) in a very unstable patient. This improved the VAD filling and flow with quick resolution of the pulmonary edema (Figure 2), therefore in a further surgery 4 days later the LA cannula was then exchanged to a Berlin Heart 9 mm atrial cannula (Figures 3 and 4) and the LV apical cannula was removed (Figure 5) and apex of the heart repaired. She was then converted back to pulsatile Berlin Bi-VAD support with this new cannulation strategy. She was well supported for 2 months only requiring one RVAD pump exchange for thrombus, however unfortunately she had infectious and neurologic complications including seizures and diminished neurologic status, which eliminated her transplant candidacy; thus support was withdrawn.
Figure 1. Axial computerized tomography (CT) scan showing markedly abnormal, diffusely calcified left ventricular wall.
Figure 2. Intraoperative photo showing the heart is rotated to the right with 9 mm Berlin inflow cannula being sewn into left atrial appendage with 5-0 prolene sutures. A. Chest X-ray showing pulmonary edema with Berlin Heart 9 mm apical LV cannulation. B. Chest X-ray showing improved pulmonary edema with Berlin Heart 9 mm LA cannulation. LA cannulation, left atrial cannulation; LV, left ventricle.
Figure 3. Intraoperative photograph showing the heart is rotated to the right with 9 mm Berlin inflow cannula being sewn into left atrial appendage with 5-0 prolene sutures.
Figure 4. Intraoperative photograph showing 9 mm Berlin inflow cannula tip positioned posteriorly and medially towards the left atrial cavity.
Figure 5. Coronal plane CT scan showing diffuse left ventricular wall calcification and both left atrial outflow and aortic inflow cannulae in position. CT, computerized tomography.
DISCUSSION
Experience with VAD support has grown tremendously in the past 10 years, with now close to 40% of pediatric patients requiring mechanical support as a bridge to transplantation.4 Despite this, patients who have restrictive physiology (diastolic heart failure) continue to be a challenge as there is often inadequate unloading of the left atrium in these cases. Although our patient presented with systolic failure, she had evidence of diastolic dysfunction secondary to a severely calcified/fibrotic ventricle. In this case, the only way to adequately unload the left atrium was with direct cannulation. However, from personal communications with Berlin Heart, we were aware of the increased risk of clot formation and thrombosis in left atrial cannulation as historically reported with the Berlin Heart Excor. This has been attributed to the turbulence of flow from LA cannulation despite optimal anticoagulation management. Despite optimal anticoagulation and no direct evidence for thrombosis in LA cannula or LVAD, this patient experienced a devastating neurologic injury that was likely multifactorial and could be secondary to an infection, hypoperfused states throughout her course, or embolic events as evidenced by head CT changes even before the LA cannulation.
In other reports, the left atrium is cannulated via the right superior pulmonary vein or with the creation of atrial septal defect (ASD) and placement of an interposition graft to the cannula.5 This approach can lead to pulmonary vein stenosis, even after a transplant, and the approach with the creation of ASD requires CPB. The alternate approach we described above avoids pulmonary vein stenosis and allows an approach from the left side to minimize the risk of superior vena caval obstruction. In addition, our approach allowed us to cannulate the LA off the bypass in an otherwise very unstable patient and we utilized the same exit point on the chest of the left ventricular apical cannula. We can argue this cannulation strategy can be expanded for adequate left-sided heart drainage and a better chance of LV recovery and probably less risk for fibrosis/calcification injury development when there is inadequate unloading of the LV.
Disclosure: SMS is a consultant for Cryolife. The other authors have no conflicts of interest to report. | DOPAMINE HYDROCHLORIDE, EPINEPHRINE | DrugsGivenReaction | CC BY-NC-ND | 33369930 | 20,907,950 | 2021-09-01 |
What is the weight of the patient? | Berlin Excor Cannulation of Left Atrial Appendage in Left Ventricular Restrictive Physiology: A Novel Bailout Strategy.
Ventricular assist device (VAD) management continues to be a challenge in the presence of restrictive physiology. Left atrial (LA) decompression is not satisfactory even with good function and position of the left ventricular cannula. We describe an alternate approach with LA cannulation via the left atrial appendage (LAA) as a rescue strategy in a patient who had restrictive physiology, in our case was secondary to viral myocarditis acute systolic heart failure with subsequent insidious diffuse endomyocardial fibrosis and superimposed massive calcification, causing inadequate emptying of the left ventricle despite optimal VAD apical cannula position.
Extracorporeal ventricular assist device (VAD) support is commonly used in young children with severe heart failure to support them to recovery or heart transplant as the children are too small to be supported with adult-type intracorporal VADs. Some pediatric centers prefer the centrimag/pedimag for short-term support given more experience with this device. However, the Berlin Heart Excor has become the preferred VAD in other centers for children who require medium to long-term VAD. As worldwide experience with this type of VAD has expanded, there have been improved outcomes1 likely related to changes in the anticoagulation management, patient selection, a better understanding of VAD management, and also attributed to increased surgical experience with the implant techniques which improves hemodynamics.
VAD management continues to be a challenge in the presence of restrictive physiology. Left atrial decompression is not satisfactory even with good function and position of the left ventricular cannula. To combat this problem, techniques have been developed to cannulate the left atrium (LA) directly, particularly in hypertrophied ventricles or when the size of the ventricle would not allow for the appropriate position of the inflow cannula.2 The surgical technique of LA cannulation has been described previously,3 and typically involves cannulation of the rightward aspect of the LA directly or via the right pulmonary vein.
Herein, we describe an alternate approach with LA cannulation via the left atrial appendage (LAA) as a rescue strategy in a patient who had restrictive physiology secondary to viral myocarditis acute systolic heart failure with subsequent insidious diffuse endomyocardial fibrosis and superimposed massive calcification, causing inadequate decompression of the left ventricle (LV) despite optimal VAD apical cannula position.
CASE REPORT
A 6-year-old, 17 kg female presented to the emergency department with fever, tachycardia, and respiratory distress. Echocardiogram revealed a severely depressed bi-ventricular function. She rapidly decompensated with the development of acute cardiorespiratory failure and required intubation, and initiation of inotropic support with dopamine and epinephrine. Progression with acute pulmonary edema and ongoing severe cardiac failure refractory to maximal medical therapy required advanced mechanical support with peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) from femoral vessels approximately 12 hours after presentation. Because of left atrial distention on echocardiography, the patient was taken to cardiac catheterization for atrial septostomy. Her medical/surgical history was significant for renal transplantation at 2 years of age secondary to congenital renal dysplasia. Her post-renal transplant course was complicated by chronic graft dysfunction secondary to recurrent antibody-mediated rejection, Epstein Barr Virus (EBV) viremia, and post-transplant lymphoproliferative disorder.
Further evaluation of her decompensation revealed most likely enteroviral myocarditis (serum PCR positive for enterovirus). On VA-ECMO, the flows were ranging from 2 to 2.5 L/minute (LPM); however, despite the atrial septostomy the patient developed pulmonary hemorrhage and echocardiography showed evidence of ongoing severe left atrial hypertension with NT-pro B-type natriuretic peptide (BNP) 91.388 pg/mL and troponin peak 151.966 µg/ml. Therefore, the patient was transitioned 10 days later from peripheral VA-ECMO to a Thoratec CentriMag (Abbott) Bi-VAD support with cannulation of the right atrium (RA)/pulmonary artery (PA) for the right VAD and the left atrium(LA)/Ascending Aorta (Ao) for the left VAD (LVAD). With this cannulation strategy, the patient was well supported with excellent oxygenation, renal function, and adequate bi-VAD flows ranging from 2 to 2.5 LPM on the LVAD and 1.5 to 2.3 LPM on the RVAD. Conversion to longer-term mechanical support was needed 2 weeks later due to lack of myocardial recovery with ongoing systolic heart failure with left ventricular ejection fraction <20% preoperative head computed tomography (CT) scan showed subacute right middle cerebral artery stroke and foci of acute intraparenchymal hemorrhage within right frontal and parietal lobes. These findings were stable on repeat head CT 1 week later, and so the decision was made to proceed with Berlin Heart Excor (Berlin Heart Inc, The Woodlands, Tx) implant. After discussion with the technical support of Berlin Heart, we opted for a 25-mL Berlin Heart Excor Bi-VAD support, via 9 mm RA and left ventricular apical cannulae, and 6 mm pulmonary artery and ascending aortic cannulae. The settings on the Berlin Heart were adjusted to maintain optimal filling and emptying of both RVAD and LVAD, with initial settings with LVAD rate: 90 BPM, systolic pressure 210, diastolic pressure −40, and 35% systole, with RVAD Rate: 87 BPM, systolic pressure 175, diastolic pressure −25 and 35% systole.
Despite initial optimal filling and emptying of both VADs, in the following days, we encountered persistent difficulty with the filling of the LVAD with worsening pulmonary edema. This inadequate filling was not responsive to any adjustments of the Berlin settings in terms of diastolic pressure, rate of the device, and synchrony between the two VADs. Furthermore, the native heart was relatively bradycardic (maximum 80 beats/minute), which notoriously is a favorable factor for Berlin LVAD mechanics. The inadequate filling was thought to be secondary to restrictive physiology from the development of diffuse endomyocardial fibrosis and massive calcifications in the left ventricle (LV) myocardium (Figure 1). Because of this, the plan was to take the patient back to the operating room to change the left side inflow cannulation from the left ventricular apex to the LA. This was accomplished with the addition of a LA cannula through the LAA and using a Y-connection with the left ventricular apical cannula to a CentriMag continuous flow pump in exchange for the Berlin left-sided pump. The RVAD was also changed to a Centrimag pump at this time. The reason this unusual configuration was adopted was to avoid another run of cardiopulmonary bypass (CPB) in a very unstable patient. This improved the VAD filling and flow with quick resolution of the pulmonary edema (Figure 2), therefore in a further surgery 4 days later the LA cannula was then exchanged to a Berlin Heart 9 mm atrial cannula (Figures 3 and 4) and the LV apical cannula was removed (Figure 5) and apex of the heart repaired. She was then converted back to pulsatile Berlin Bi-VAD support with this new cannulation strategy. She was well supported for 2 months only requiring one RVAD pump exchange for thrombus, however unfortunately she had infectious and neurologic complications including seizures and diminished neurologic status, which eliminated her transplant candidacy; thus support was withdrawn.
Figure 1. Axial computerized tomography (CT) scan showing markedly abnormal, diffusely calcified left ventricular wall.
Figure 2. Intraoperative photo showing the heart is rotated to the right with 9 mm Berlin inflow cannula being sewn into left atrial appendage with 5-0 prolene sutures. A. Chest X-ray showing pulmonary edema with Berlin Heart 9 mm apical LV cannulation. B. Chest X-ray showing improved pulmonary edema with Berlin Heart 9 mm LA cannulation. LA cannulation, left atrial cannulation; LV, left ventricle.
Figure 3. Intraoperative photograph showing the heart is rotated to the right with 9 mm Berlin inflow cannula being sewn into left atrial appendage with 5-0 prolene sutures.
Figure 4. Intraoperative photograph showing 9 mm Berlin inflow cannula tip positioned posteriorly and medially towards the left atrial cavity.
Figure 5. Coronal plane CT scan showing diffuse left ventricular wall calcification and both left atrial outflow and aortic inflow cannulae in position. CT, computerized tomography.
DISCUSSION
Experience with VAD support has grown tremendously in the past 10 years, with now close to 40% of pediatric patients requiring mechanical support as a bridge to transplantation.4 Despite this, patients who have restrictive physiology (diastolic heart failure) continue to be a challenge as there is often inadequate unloading of the left atrium in these cases. Although our patient presented with systolic failure, she had evidence of diastolic dysfunction secondary to a severely calcified/fibrotic ventricle. In this case, the only way to adequately unload the left atrium was with direct cannulation. However, from personal communications with Berlin Heart, we were aware of the increased risk of clot formation and thrombosis in left atrial cannulation as historically reported with the Berlin Heart Excor. This has been attributed to the turbulence of flow from LA cannulation despite optimal anticoagulation management. Despite optimal anticoagulation and no direct evidence for thrombosis in LA cannula or LVAD, this patient experienced a devastating neurologic injury that was likely multifactorial and could be secondary to an infection, hypoperfused states throughout her course, or embolic events as evidenced by head CT changes even before the LA cannulation.
In other reports, the left atrium is cannulated via the right superior pulmonary vein or with the creation of atrial septal defect (ASD) and placement of an interposition graft to the cannula.5 This approach can lead to pulmonary vein stenosis, even after a transplant, and the approach with the creation of ASD requires CPB. The alternate approach we described above avoids pulmonary vein stenosis and allows an approach from the left side to minimize the risk of superior vena caval obstruction. In addition, our approach allowed us to cannulate the LA off the bypass in an otherwise very unstable patient and we utilized the same exit point on the chest of the left ventricular apical cannula. We can argue this cannulation strategy can be expanded for adequate left-sided heart drainage and a better chance of LV recovery and probably less risk for fibrosis/calcification injury development when there is inadequate unloading of the LV.
Disclosure: SMS is a consultant for Cryolife. The other authors have no conflicts of interest to report. | 17 kg. | Weight | CC BY-NC-ND | 33369930 | 20,907,950 | 2021-09-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ankle fracture'. | Safety and Effectiveness of an All-Oral, Bedaquiline-Based, Shorter Treatment Regimen for Rifampicin-Resistant Tuberculosis in High Human Immunodeficiency Virus (HIV) Burden Rural South Africa: A Retrospective Cohort Analysis.
At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.
We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database.
Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants.
An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.
pmcRifampicin-resistant tuberculosis (RR-TB) affects over half a million of people each year. South Africa remains among the countries with the highest TB and RR-TB burden in the world, with an estimated incidence of 520 TB cases per 100 000 in 2018, up to 7% of which are rifampicin-resistant [1]. The treatment of RR-TB can be long and complex, associated with toxic agents, yet with treatment success rates remaining at just over 60% [2–4]. New and repurposed drugs are now available, with South Africa rolling out new regimens in recent years. South African programmatic data were used to update the World Health Organization (WHO) recommendations for the treatment of RR-TB in 2018 and 2019. This led to the most recent WHO recommendation for an all-oral shorter regimen in which bedaquiline (BDQ) replaces the injectable [5]. This regimen, however, still includes ethionamide (ETH), a drug with doubtful efficacy, poorly tolerated by patients, and ranked lower than linezolid (LZD) in the WHO RR-TB drug hierarchy. Linezolid, a drug shown to be associated with better outcomes and lower mortality, is currently still excluded from the WHO-recommended shorter regimen [5, 6]. At the end of 2018, South Africa modified its all-oral regimen, recommending 6 months of BDQ and 2 months of LZD for all patients initiating the shorter 9–12 months RR-TB regimen [7]. We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this “newest” treatment regimen under programmatic conditions.
METHODS
Study Design
This is a retrospective cohort analysis of routinely collected programmatic data of RR-TB patients eligible for a short standardized BDQ-based regimen between 1 July 2018 and 30 April 2019 [7]. Study was conducted at 3 RR-TB facilities in King Cetshwayo District, KwaZulu Natal, South Africa.
Study Setting
King Cetshwayo District has a human immunodeficiency virus (HIV) prevalence of 26.4% in the general population and RR-TB rates of 9–12% among all TB cases [8, 9]. In 2011, Médecins sans Frontières (MSF) began working with the National Department of Health (NDoH) and District Health teams to support decentralization of RR-TB care and to improve access to new regimens. Since 2016, RR-TB treatment is provided at 3 ambulatory sites with a centralized in-patient unit if admission is clinically indicated.
RR-TB Treatment Protocol
On diagnosis of rifampicin resistance (by nucleic acid amplification test [GeneXpert; Cepheid] or line probe assay test [GenoType MTBDRplusV2.0; Hain Lifescience]), patients receive clinical evaluation, baseline examinations, and treatment initiation according to NDoH Guidance at a RR-TB treatment site [7]. One sputum sample is collected for smear, culture, and first- and second-line genotypic resistance testing (culture, GenoType MTBDRplus and GenoType MTBDRsl assay are processed by the referral laboratory of the National Health Laboratory Service [NHLS]). This forms the baseline culture for the patient and is taken within the timeframe of 3 months before to 1 month after treatment start.
The South African standard of care for RR-TB changed during 2018. In July, a BDQ-based regimen was implemented. ETH was removed during the following months (some still receiving ETH initially), and it was advised to treat with LZD until second-line resistance could be excluded. This led to variable durations of LZD among patients. In November 2018, a generalized recommendation of 2 months of LZD for all patients initiating RR-TB treatment was released [7] (Figure 2). In patients with hemoglobin levels <8g/dL, LZD initiation is deferred until anemia improves, sometimes requiring blood transfusion.
Figure 2. Diagrammatic overview of the short standardized Bedaquiline-based regimen, indicating recommended duration of each drug as of November 2018 in South Africa (National Department of Health Interim Guidance for the Implementation of Injectable Free Regimens for Rifampicin-Resistant Tuberculosis).
First follow-up of patients happens 2 weeks after initiation. Specific laboratory tests, including full blood and neutrophil count, are recommended, as well as electrocardiogram (ECG) monitoring. Further follow-ups are at week 4 and then monthly, with regular ECG while on BDQ and laboratory tests indicated by the prescribed medications. Monthly bacteriological monitoring consists of both smear and culture (SC) samples for all patients on treatment. Cultures are done by liquid medium (BACTEC MGIT®). Phenotypic drug susceptibility testing (DST) for first- and second-line drugs happens on all positive cultures. Adverse events (AEs) are managed according to their clinical significance and national guidelines [7].
Study Population
We included all RR-TB patients over 18 years of age, eligible for the short standardized all-oral BDQ-based regimen as per NDoH guidance [7], at Eshowe, Mbongolwane, and Catherine Booth hospitals in King Cetshwayo District between 1 July 2018 and 30 April 2019.
Study Variables and Definitions
WHO and national guidelines were used to define RR-TB resistance type and outcome variables such as time to SC conversion, end-of-treatment outcomes, and AEs [7, 10]. Time to SC conversion was defined as the time from initiation of RR-TB treatment to time of SC conversion. SC conversion was reached with 2 consecutive negative SC results on samples collected at least 30 days apart with conversion date being the collection date of the first negative SC sample [10].
End-of-treatment outcomes were assigned by the treating clinician, in line with both NDoH and WHO definitions [7]. An AE is defined as any “untoward medical occurrence in a patient receiving any kind of treatment” [11]. We looked at AEs up until the end of the 24-week BDQ course. AEs are graded on a scale of 1 to 4, with 1 being mild and 4 being life-threatening [11]. AEs of grade 3 and higher are considered severe. AEs occurring more than once in the same patient were recorded by the date of highest severity. AEs leading to persistent disability or hospitalization were noted as serious AEs. It was difficult, however, to conclude occurrence of AEs as causes of death due to incompleteness of AE reporting, to polypharmacy and comorbidities of patients, and unspecified recording on death certificates. QT intervals are calculated according to Frederica’s formula (QTcF) as recommended per national guidelines [7]. Specific cutoff values for numeric variables of laboratory tests to define grading are taken from the Clinical and Programmatic Guide for Patient Management with New TB Drugs (Common Terminology Criteria for Adverse Events [CTCAE] v.4.03 classification) [11]. For the entire cohort, 2 same medical doctors interpreted treating clinicians’ notes for grading of AEs. All pro-formas were checked for completeness by the principal investigator before final recording.
Data Collection and Analysis
Source documents for our study were NDoH Electronic Drug-resistant Tuberculosis Register (EDRWeb), NHLS results, and facility-based clinical charts. Data were extracted by using a standardized data collection tool (see the Supplementary material). All data were entered into an Epi-Info (Centers for Disease Control and Prevention [CDC], Atlanta, GA, USA) database. Continuous variables are presented as medians with interquartile range (IQR). Categorical variables are presented as frequencies and proportions. A χ 2 test was used to compare categorical variables. Time to SC conversion was estimated using Kaplan-Meier (KM) curves. For the analysis of time to SC conversion, the outcome of interest was SC conversion achieved within 3 or 6 months of treatment. If the outcome of interest was not achieved, it was considered as censored.
Censoring occurs when the patient is lost to follow-up (LTFU) or died before achieving SC conversion. The time of censoring was the date of death or LTFU. Censoring also occurred when the patient did not SC convert within 6 months of treatment or transferred or moved out (TMO) before SC conversion was achieved. In our cohort, however, no patient TMO before SC conversion was achieved, and SC conversion status at month 6 was known for all those with positive baseline SC samples. Log-rank test was used to investigate the difference between survival curves. The median time to SC conversion was reported using 95% confidence interval (CI). Data were analyzed using STATA version 15 (StataCorp, College Station, TX, USA).
Ethics
Ethics approval was obtained by MSF Ethics Review Board (Geneva, Switzerland) and the Biomedical Research Ethics Board of the University of KwaZulu-Natal, South Africa.
RESULTS
Patient Characteristics
From 1 July 2018 to 30 April 2019, 194 patients were notified with RR-TB in our district. The short regimen was initiated in 151 patients, yet 19.9% (30/151) were switched to a longer regimen, when their baseline resistance profiles became available, as per NDoH guidelines. Figure 1 shows the patients eligible for the short standardized BDQ-based course included in the final analysis.
Figure 1. Flow diagram of selection of study participants from patients notified with RR-TB in King Cetshwayo district, Kwa-Zulu Natal, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: DR-TB, drug-resistant tuberculosis; INH, isoniazid; RR-TB, rifampicin-resistant tuberculosis.
Table 1 shows the baseline characteristics of these 117 patients. Of our patients, 59.8% (95% CI: 50.6–68.4) were male, 68.4% (95% CI: 59.3–76.3) living with HIV, and 55.6% (95% CI: 46.3–64.4) had confirmed multidrug resistance (MDR). Of our cohort, 91.5% (95% CI: 84.7–95.4) received both BDQ and LZD; the median time on LZD was 8 (IQR: 6–13) weeks. And 76.9% (95% CI: 68.3–83.6) received their complete RR-TB treatment as out-patients.
Table 1. Demographic and Clinical Characteristics of RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019, n = 117
Patients Characteristics n %/Median 95% CI/IQR
Gender
Female 47 40.2 31.6–49.4
Male 70 59.8 50.6–68.4
Median age (IQR) 117 35 27–44
Age group
14–24 22 18.8 12.6–27.0
25–34 33 28.2 20.7–37.2
35–44 34 29.1 21.5–38.0
45–54 17 14.5 9.2–22.3
≥55 11 9.4 5.2–16.3
Previous TB history
New 63 53.8 44.7–62.8
Had DSTB 50 42.7 34.0–52.0
Had DRTB 4 3.4 1.7–8.9
HIV status
Negative 37 31.6 23.7–40.7
Positive 80 68.4 59.3–76.3
ART status during RR-TB Tx (n = 80)
Lost to follow-up 6 7.5 3.3–15.9
Newly diagnosed 12 15.0 8.6–24.8
Stable on antiretroviral 62 77.5 66.8–85.5
Median CD4 at RR-TB initiation (IQR) 76 243 93–459
CD4 at RR-TB initiation (n = 80)
<100 20 25.0 16.6–35.9
100–200 16 20.0 12.5–30.4
200–350 14 17.5 10.5–27.7
≥350 26 32.5 23.0–43.7
CD4 not done 4 5.0 1.8–12.8
RR-TB type
Rif Res on GXP only 39 33.3 25.3–42.5
Rif monoresistance 11 9.4 5.2–16.3
GXP: Rif Res and 1st line LPA sensitive 2 1.7 .4–6.7
Confirmed MDRa 65 55.6 46.3–64.4
Baseline smear results
Negative 63 53.8 44.7–62.8
Positive 52 44.4 35.6–53.7
Test not done 2 1.7 .4–6.7
Baseline culture results
Negative 32 27.4 19.9–36.3
Positive 67 57.3 48.0–66.0
Contaminated 12 10.3 5.9–17.3
Test not done 6 5.1 2.3–11.1
Hb at baseline
<7.9 9 7.7 4.0–14.2
7.9–9.9 26 22.2 15.5–30.8
≥10 82 70.1 61.1–77.8
QTcF at baseline
<450 112 95.7 90.0–98.2
≥450 4 3.4 1.3–8.9
Missing 1 0.9 .1–6.0
Abbreviations: ART, antiretroviral therapy; BDQ, bedaquiline; CI, confidence interval; GXP, GeneXpert (first line test for any presumptive TB case); Hb, hemoglobin; HIV, human immunodeficiency virus; INH, isoniazid; IQR, interquartile range; LPA, line probe assay; MDR, multidrug resistant (resistant to both rifampicin and isoniazid); QTcF, calculated QT interval according to Frederica’s formula; Rif Res, rifampicin resistant; Rif S, rifampicin sensitive; RR-TB, rifampicin-resistant tuberculosis; TB, tuberculosis.
aIsoniazid resistance in these patients was limited to the presence of a single gene mutation (either katG or inhA), because patients with both mutations do not qualify to receive the shorter regimen [7].
Bacteriological Outcomes
Among 117 patients, 44.4% (95% CI: 35.6–53.7) had a positive smear and 57.3% (95% CI: 48.0–66.0) a positive culture at baseline. And 95 patients (81.2%) completed 6 months of treatment and had a median number of monthly follow-up smear and culture results of 6 (IQR 5–6) and 5 (IQR 4–6), respectively (Table 2). Smear conversion was achieved in 92.3% (95% CI: 80.7–97.2), and 7.7% (95% CI: 2.8–19.3) died within 6 months. Culture conversion was achieved in 89.6% (95% CI: 79.3–95.0), 6.0% (95% CI: 2.2–15.2) died, and 4.5% (95% CI: 1.4–13.3) LTFU within 6 months. The median time to smear conversion was 34 days (95% CI: 29–45) and to culture conversion 56 days (95% CI: 50–57) (Figure 3).
Table 2. Smear and Culture Conversion Status at Month 6 for RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019.
Smear and Culture Follow-up and Conversion Status at Month 6 of Treatment n %/Median 95% CI/IQR
Median number of follow-up smears for all 95 6 5–6
Median number of follow-up smears for smear positive at baseline 41 6 5–6
Smear conversion status (n = 52)
Converted negative 48 92.3 80.7–97.2
Died before conversion 4 7.7 2.8–19.3
LTFU before conversion 0 0.0 N/A
Median number of follow-up cultures for all 95 5 4–6
Median number of follow-up cultures for culture positive at baseline 56 5 4–6
Culture conversion status (n = 67)
Converted negative 60 89.6 79.3–95.0
Died before conversion 4 6.0 2.2–15.2
LTFU before conversion 3 4.5 1.4–13.3
Of total cohort (n = 117), 95 completed 6 months treatment. Of 67 culture positive at baseline, 56 completed 6 months treatment. Of 52 smear positive at baseline, 48 completed 6 months treatment.
Abbreviations: BDQ, bedaquiline; CI, confidence interval; IQR, interquartile range; LTFU, lost to follow-up; N/A, not applicable; RR-TB, rifampicin-resistant tuberculosis.
Figure 3. Kaplan-Meier survival estimates for smear/culture positive RR-TB patients at baseline in King Cetshwayo district, 1 July 2018 to 30 April 2019. A, Time to culture conversion (n = 67). B, Time to smear conversion (n = 52). C, Time to culture conversion by HIV status (n = 67); log-rank test within 6 months of follow-up: P = .104. D, Time to culture conversion by CD4 count (n = 45); log-rank test within 3 months of follow-up: P = .826. Abbreviations: HIV, human immunodeficiency virus; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in HIV-negative patients compared to HIV-positive was 90.0% (95% CI: 64.5–97.8) versus 89.4% (95% CI: 76.2–95.7) (P = .938) (Table 3). The median time to culture conversion for HIV-negative and HIV-positive patients was 36 (95% CI: 29–57) and 57 days (95% CI: 53–64), respectively (P = .104) (Figure 3).
Table 3. Culture Conversion Status at Month 6 of Treatment for HIV-positive Patients with Positive Baseline Culture by HIV status and CD4 Cell Count of RR-TB Patients Initiated and Continued on the Short Standardized BDQ-based Regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019
HIV negative (n = 20) HIV positive (n = 45) CD4 <200 cells/µL (n = 20) CD4 ≥200 cells/µL (n = 25)
Culture Conversion Status at Month 6 n % 95% CI n % 95% CI n % 95% CI n % 95% CI
Converted negative 18 90.0 64.5–97.8 42 89.4 76.2–95.7 17 85.0 59.6–95.6 24 96.0 73.7–99.5
Died before conversion 2 10.0 2.2–35.5 2 4.3 1.0–16.2 1 5.0 .5–32.3 1 4.0 .4–26.3
LTFU before conversion 0 0.0 0.0–0.0 3 6.4 2.0–18.7 2 10.0 2.0–35.5 0 0.0 0–0
χ 2 and P value: HIV-negative vs HIV-positive (.006 and .938). CD4 <200 vs ≥200 (1.66 and .198).
Abbreviations: BDQ, bedaquiline; CI, confidence interval; HIV, human immunodeficiency virus; LTFU, lost to follow-up; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in CD4 count <200 cells/µL compared to CD4 count ≥200 cells/µL was 85.0% (95% CI: 59.6–95.6) versus 96.0% (95% CI: 73.7–99.5) (P = .198) (Table 3). We looked at time to culture conversion up to 3 months considering that 3-months culture conversion was known for 82.2% (95% CI: 67.9–92.0) of patients living with HIV with documented baseline CD4. There was no significant difference between KM survival curves of CD4 groups within 3 months of follow-up (P = .826) (Figure 3). The median time to culture conversion within 6 months follow-up in CD4 levels <200 cells/µL was 64 days (95% CI: 32–113) and with CD4 levels ≥200 cells/µL was 57 days (95% CI: 57–68).
Seven patients had a positive culture during their treatment course after achieving culture conversion. Four of the 7 positive cultures occurred after month 6. The positive cultures showed similar resistance patterns to baseline and patients continued the same regimen. All 7 patients reconverted; 5 successfully completed treatment, 1 patient had TMO, and 1 patient was LTFU. Of patients with negative baseline culture samples, 7 developed a positive culture during treatment. Of these 7, 2 patients had culture results with amplified resistance profiles, compared to baseline line probe assay results.
End-of-Treatment Outcomes
Treatment success was achieved in 75.2% (95% CI: 66.5–82.3) of patients. Mortality was 12.8% (95% CI: 7.8–20.3), and 80% (95% CI: 51.9–95.7) of deaths occurred in the first 4 months of treatment. LTFU, treatment failure, and TMO was recorded in 10.3% (95% CI: 5.9–17.3), .9% (95% CI: .01–6.0), and .9% (95% CI: .01–6.0), respectively.
Adverse Events
A total of 298 AEs was recorded; 108 (92.3% [95% CI: 85.8–96.0]) patients experienced at least 1 AE (grade 1–4) during the BDQ course, with a median of 2 (IQR 2–4) AEs per patient. Looking at severe AEs only, a total of 62 severe AEs were recorded in 43 (36.8% [95% CI: 28.4–46.0]) patients. Anemia was the most frequent and accounted for 27 (43.5% [95% CI: 31.0–56.7]) of all severe AEs (Figure 4). For these 27 patients, the median time to severe anemia was 7.1 (IQR 4.0–12.9) weeks after treatment initiation. Of 107 patients who received LZD, 27 (25.2% [95% CI: 17.3–34.6]) developed severe anemia. Of 15 patients who died, severe anemia occurred in 10 (66.7% [95% CI: 38.4–88.2]) patients. In our cohort, grade 3 and 4 QT prolongation occurred in 7 (6.0% [95% CI: 2.4–11.9]) patients. Other severe AEs documented were hepatotoxicity in 9 (14.5% [95% CI: 6.9–25.8]) patients, QT prolongation in 7 (11.3% [95% CI: 4.7–21.9]) patients, nausea and vomiting in 5 (8.1% [95% CI: 2.7–17.8]) patients, and nephrotoxicity in 4 (6.5% [95% CI: 1.8–15.7]) patients. One patient developed optic neuritis and lost all vision. A different patient developed peripheral neuropathy of the lower limbs and fractured her ankle following gait disturbances. These last 2 AEs met the definition of serious AEs.
Figure 4. Frequency of severe AEs experienced in RR-TB patients during first 24 weeks after treatment initiation (N = 62), receiving a short standardized BDQ-based regimen in King Cetshwayo district between 1 July 2018 and 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; RR-TB, rifampicin-resistant tuberculosis.
Management of Adverse Events
Supportive medication was given for symptom control for 103 (34.6% [95% CI: 29.2–40.3]) AEs. No specific management actions were taken for 119 (39.9% [34.3–45.7]) AEs, due to their transient course, clinical insignificance, and/or planned completion of the course of the causative drug. For 21 (7.0% [95% CI: 4.4–10.6]) AEs, patients were hospitalized for further monitoring and treatment.
Hospitalization after treatment initiation occurred in 26 (22.2% [95% CI: 15.1–30.8]) of our patients for various reasons. Among hospitalizations, 18 (69.2% [95% CI: 48.2–85.7]) were attributed to an AE and the need for inpatient management. Of these AE-linked admissions, 8 (44.4% [95% CI: 21.5–69.2]) were due to severe anemia, and 2 (11.1% [95% CI: 1.4–34.7]) were due to a prolonged QT interval.
LZD was interrupted by the provider in 27 (25.2% [95% CI: 17.8–34.5]) participants; the median time on LZD for these patients was 8 (IQR 4–11) weeks. LZD was reintroduced at a reduced dosage of 300 mg/day in 8 occurrences; 1 patient reinitiated the dosage of 600 mg/day; in the remaining 18 cases, LZD was permanently discontinued and not replaced. This was due to various reasons, including receipt of DST results showing an absence of second-line resistance or clinical improvement of the patient on the regimen, where the risks of LZD were felt to outweigh the benefit of continued use. BDQ was interrupted in 3 patients and reinitiated in all, after review and supportive therapy.
DISCUSSION
The South African all-oral short regimen shows good results in a high HIV burden setting. Treatment success was achieved in 75% of our patients, exceeding historical treatment successes of <65% of both the short injectable regimen and the “BLIX” cohort (BDQ and LZD for XDR patients) within the same area [12, 13]. The success rate is similar to that reported from a national cohort in South Africa where BDQ and LZD were combined in a longer regimen [14]. AEs remain common and were often associated with the use of LZD, but some toxicity occurred to other drugs in the regimen. High-dose isoniazid, pyrazinamide, and ethambutol were frequently interrupted following an AE (Figure 5), calling into question the routine use of these drugs for RR-TB treatment, as their effectiveness is also uncertain [6]. Mortality in our cohort remains high, comparable to other oral regimens for RR-TB [14, 16] and happens early during treatment. This can be due to delayed diagnosis and treatment initiation [17]. Most of our patients received their treatment as outpatients, likely reducing costs within a resource-limited healthcare system yet with risk for LTFU, in absence of proper financial and social support.
Figure 5. Graphic illustration of episodes of treatment interruption (N = 94) per individual drug (drug name; n) following an AE in patients during the first 24 weeks of the short standardized BDQ-based regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; CLF, clofazimine; E, ethambutol; ETH, ethionamide; INH hd, high dose isoniazid; LFX, levofloxacin; LZD, linezolid; PZA, pyrazinamide.
Almost 20% of patients initiated on the short regimen were switched to a longer regimen when their baseline resistance profiles became available [7]. We decided not to include these patients in our analysis, as we wanted to assess both tolerability and effectiveness in the “newest” shorter regimen for eligible RR-TB patients. These 30 patients either had isoniazid (INH) mutations and/or levofloxacin or injectable resistance. Although excluded from our analysis, they represent an important population for additional future study, especially to see if the empiric inclusion of LZD as part of the shorter regimen decreases the likelihood of developing resistance to other administered drugs. As patients are currently started on RR-TB treatment before rapid molecular INH and FLQ-resistance results are available, we believe there is benefit in a robust regimen, including LZD, at treatment initiation.
Nearly all of our patients received both BDQ and LZD. The use of these 2 drugs likely contributed to high rates of almost 90% of SC conversion at month 6, exceeding conversion rates in similar settings [18]. LZD has been associated with improved outcomes in RR-TB patients [3, 19] and adding on LZD to the BDQ-based regimen, forming a robust backbone, could have contributed to the rapid time to culture conversion in our cohort. Our results are consistent with those reported under trial conditions, but they are noteworthy, demonstrating what can be achieved in program conditions with high HIV comorbidity [3, 18, 20–25] present. An important finding in our cohort is that HIV status and CD4 levels had no effect on achieving culture conversion, or on time needed to convert within the first 3 months of treatment, even though almost half of our HIV-positive cohort had advanced HIV disease. We acknowledge our small sample size and are cautious drawing conclusions from our findings; nevertheless, this is encouraging for other countries with high HIV/DRTB burden.
Worldwide concern for BDQ-related cardiotoxicity has promoted frequent ECG monitoring [5, 7], yet QT prolongation was observed in <10.0% of the cohort and contributed minimally to hospitalizations. The safety of BDQ has been reinforced in both HIV-negative and HIV-positive patients over the past few years and we see the same reassuring results [20, 26]. LZD-related toxicities, however, remained a challenge, equally noted in other settings [15, 19, 20, 23]. Anemia was the most frequent recorded severe AE, contributing to treatment discontinuation, hospitalization, and possibly mortality within our cohort. Most of the LZD-related toxicities reversed when the drug was discontinued. The overall frequency of peripheral neuropathy in our cohort is low, as LZD exposure was limited to 2 months and possibly underdiagnosis of the pathology. Considering all LZD-associated toxicities, it is crucial to strictly monitor for myelosuppression and neuropathy and to ensure prompt management happens when toxicity occurs [5, 7, 27].
There are several limitations to our analysis. We look at the cohort retrospectively without any comparison group and therefore cannot exclude a general improvement of care contributing to our results. Our cohort was defined as the patients receiving the newly adopted “all-oral BDQ-based” regimen in South Africa, yet the guidance and final recommendation for this regimen was delayed. This led to variable durations of LZD within our cohort. Our data likely underreport on AEs because we relied on routine program data, characterized by inaccuracies in recording. Trained clinicians performed a systematic audit on all clinical charts and missing laboratory results were retrieved online to minimize incompleteness. Retrieving information on AEs a posteriori made it difficult to conduct any causality assessment. We assessed end-of-treatment outcomes with no further follow-up of our cohort and have no data on recurrence rates of this regimen; final outcomes could differ. Fourteen patients had a positive culture, mostly late in treatment, and could be at higher risk for relapse. Long-term follow-up of RR-TB patients completing treatment is necessary to evaluate relapse risk and long-term effectiveness of the shorter regimen.
CONCLUSION
An all-oral shorter regimen, containing BDQ and LZD, shows excellent outcomes in a high HIV prevalent population and used under rural programmatic conditions. The most common AEs were related to LZD, and specific screening and management strategies are needed to identify bone marrow toxicity, especially after the first month of treatment, associated with this medication. In spite of the effectiveness of this regimen, mortality remained high and there is additional support needed to reduce LTFU as well.
South Africa has shown a way for rapid implementation of new regimens under programmatic conditions, using WHO group A drugs to combat their RR-TB epidemic. Given the effectiveness and the feasibility of this regimen, the country can hopefully serve as a model for others to improve RR-TB care for patients worldwide.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ciaa1894_suppl_Supplementary_Material Click here for additional data file.
Notes
Acknowledgments. We would like to acknowledge our patients for their trust in the treating healthcare practitioners, our colleagues from the Department of Health working in RR-TB units implementing new guidelines, and all data encoders at Médecins sans Frontières offices for their work.
Financial support. No external funding was used for this analysis. All work was performed under the usual duties of the Médecins sans Frontières staff.
Potential conflict of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. | BEDAQUILINE, LINEZOLID | DrugsGivenReaction | CC BY-NC-ND | 33372989 | 20,471,124 | 2021-11-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blindness'. | Safety and Effectiveness of an All-Oral, Bedaquiline-Based, Shorter Treatment Regimen for Rifampicin-Resistant Tuberculosis in High Human Immunodeficiency Virus (HIV) Burden Rural South Africa: A Retrospective Cohort Analysis.
At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.
We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database.
Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants.
An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.
pmcRifampicin-resistant tuberculosis (RR-TB) affects over half a million of people each year. South Africa remains among the countries with the highest TB and RR-TB burden in the world, with an estimated incidence of 520 TB cases per 100 000 in 2018, up to 7% of which are rifampicin-resistant [1]. The treatment of RR-TB can be long and complex, associated with toxic agents, yet with treatment success rates remaining at just over 60% [2–4]. New and repurposed drugs are now available, with South Africa rolling out new regimens in recent years. South African programmatic data were used to update the World Health Organization (WHO) recommendations for the treatment of RR-TB in 2018 and 2019. This led to the most recent WHO recommendation for an all-oral shorter regimen in which bedaquiline (BDQ) replaces the injectable [5]. This regimen, however, still includes ethionamide (ETH), a drug with doubtful efficacy, poorly tolerated by patients, and ranked lower than linezolid (LZD) in the WHO RR-TB drug hierarchy. Linezolid, a drug shown to be associated with better outcomes and lower mortality, is currently still excluded from the WHO-recommended shorter regimen [5, 6]. At the end of 2018, South Africa modified its all-oral regimen, recommending 6 months of BDQ and 2 months of LZD for all patients initiating the shorter 9–12 months RR-TB regimen [7]. We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this “newest” treatment regimen under programmatic conditions.
METHODS
Study Design
This is a retrospective cohort analysis of routinely collected programmatic data of RR-TB patients eligible for a short standardized BDQ-based regimen between 1 July 2018 and 30 April 2019 [7]. Study was conducted at 3 RR-TB facilities in King Cetshwayo District, KwaZulu Natal, South Africa.
Study Setting
King Cetshwayo District has a human immunodeficiency virus (HIV) prevalence of 26.4% in the general population and RR-TB rates of 9–12% among all TB cases [8, 9]. In 2011, Médecins sans Frontières (MSF) began working with the National Department of Health (NDoH) and District Health teams to support decentralization of RR-TB care and to improve access to new regimens. Since 2016, RR-TB treatment is provided at 3 ambulatory sites with a centralized in-patient unit if admission is clinically indicated.
RR-TB Treatment Protocol
On diagnosis of rifampicin resistance (by nucleic acid amplification test [GeneXpert; Cepheid] or line probe assay test [GenoType MTBDRplusV2.0; Hain Lifescience]), patients receive clinical evaluation, baseline examinations, and treatment initiation according to NDoH Guidance at a RR-TB treatment site [7]. One sputum sample is collected for smear, culture, and first- and second-line genotypic resistance testing (culture, GenoType MTBDRplus and GenoType MTBDRsl assay are processed by the referral laboratory of the National Health Laboratory Service [NHLS]). This forms the baseline culture for the patient and is taken within the timeframe of 3 months before to 1 month after treatment start.
The South African standard of care for RR-TB changed during 2018. In July, a BDQ-based regimen was implemented. ETH was removed during the following months (some still receiving ETH initially), and it was advised to treat with LZD until second-line resistance could be excluded. This led to variable durations of LZD among patients. In November 2018, a generalized recommendation of 2 months of LZD for all patients initiating RR-TB treatment was released [7] (Figure 2). In patients with hemoglobin levels <8g/dL, LZD initiation is deferred until anemia improves, sometimes requiring blood transfusion.
Figure 2. Diagrammatic overview of the short standardized Bedaquiline-based regimen, indicating recommended duration of each drug as of November 2018 in South Africa (National Department of Health Interim Guidance for the Implementation of Injectable Free Regimens for Rifampicin-Resistant Tuberculosis).
First follow-up of patients happens 2 weeks after initiation. Specific laboratory tests, including full blood and neutrophil count, are recommended, as well as electrocardiogram (ECG) monitoring. Further follow-ups are at week 4 and then monthly, with regular ECG while on BDQ and laboratory tests indicated by the prescribed medications. Monthly bacteriological monitoring consists of both smear and culture (SC) samples for all patients on treatment. Cultures are done by liquid medium (BACTEC MGIT®). Phenotypic drug susceptibility testing (DST) for first- and second-line drugs happens on all positive cultures. Adverse events (AEs) are managed according to their clinical significance and national guidelines [7].
Study Population
We included all RR-TB patients over 18 years of age, eligible for the short standardized all-oral BDQ-based regimen as per NDoH guidance [7], at Eshowe, Mbongolwane, and Catherine Booth hospitals in King Cetshwayo District between 1 July 2018 and 30 April 2019.
Study Variables and Definitions
WHO and national guidelines were used to define RR-TB resistance type and outcome variables such as time to SC conversion, end-of-treatment outcomes, and AEs [7, 10]. Time to SC conversion was defined as the time from initiation of RR-TB treatment to time of SC conversion. SC conversion was reached with 2 consecutive negative SC results on samples collected at least 30 days apart with conversion date being the collection date of the first negative SC sample [10].
End-of-treatment outcomes were assigned by the treating clinician, in line with both NDoH and WHO definitions [7]. An AE is defined as any “untoward medical occurrence in a patient receiving any kind of treatment” [11]. We looked at AEs up until the end of the 24-week BDQ course. AEs are graded on a scale of 1 to 4, with 1 being mild and 4 being life-threatening [11]. AEs of grade 3 and higher are considered severe. AEs occurring more than once in the same patient were recorded by the date of highest severity. AEs leading to persistent disability or hospitalization were noted as serious AEs. It was difficult, however, to conclude occurrence of AEs as causes of death due to incompleteness of AE reporting, to polypharmacy and comorbidities of patients, and unspecified recording on death certificates. QT intervals are calculated according to Frederica’s formula (QTcF) as recommended per national guidelines [7]. Specific cutoff values for numeric variables of laboratory tests to define grading are taken from the Clinical and Programmatic Guide for Patient Management with New TB Drugs (Common Terminology Criteria for Adverse Events [CTCAE] v.4.03 classification) [11]. For the entire cohort, 2 same medical doctors interpreted treating clinicians’ notes for grading of AEs. All pro-formas were checked for completeness by the principal investigator before final recording.
Data Collection and Analysis
Source documents for our study were NDoH Electronic Drug-resistant Tuberculosis Register (EDRWeb), NHLS results, and facility-based clinical charts. Data were extracted by using a standardized data collection tool (see the Supplementary material). All data were entered into an Epi-Info (Centers for Disease Control and Prevention [CDC], Atlanta, GA, USA) database. Continuous variables are presented as medians with interquartile range (IQR). Categorical variables are presented as frequencies and proportions. A χ 2 test was used to compare categorical variables. Time to SC conversion was estimated using Kaplan-Meier (KM) curves. For the analysis of time to SC conversion, the outcome of interest was SC conversion achieved within 3 or 6 months of treatment. If the outcome of interest was not achieved, it was considered as censored.
Censoring occurs when the patient is lost to follow-up (LTFU) or died before achieving SC conversion. The time of censoring was the date of death or LTFU. Censoring also occurred when the patient did not SC convert within 6 months of treatment or transferred or moved out (TMO) before SC conversion was achieved. In our cohort, however, no patient TMO before SC conversion was achieved, and SC conversion status at month 6 was known for all those with positive baseline SC samples. Log-rank test was used to investigate the difference between survival curves. The median time to SC conversion was reported using 95% confidence interval (CI). Data were analyzed using STATA version 15 (StataCorp, College Station, TX, USA).
Ethics
Ethics approval was obtained by MSF Ethics Review Board (Geneva, Switzerland) and the Biomedical Research Ethics Board of the University of KwaZulu-Natal, South Africa.
RESULTS
Patient Characteristics
From 1 July 2018 to 30 April 2019, 194 patients were notified with RR-TB in our district. The short regimen was initiated in 151 patients, yet 19.9% (30/151) were switched to a longer regimen, when their baseline resistance profiles became available, as per NDoH guidelines. Figure 1 shows the patients eligible for the short standardized BDQ-based course included in the final analysis.
Figure 1. Flow diagram of selection of study participants from patients notified with RR-TB in King Cetshwayo district, Kwa-Zulu Natal, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: DR-TB, drug-resistant tuberculosis; INH, isoniazid; RR-TB, rifampicin-resistant tuberculosis.
Table 1 shows the baseline characteristics of these 117 patients. Of our patients, 59.8% (95% CI: 50.6–68.4) were male, 68.4% (95% CI: 59.3–76.3) living with HIV, and 55.6% (95% CI: 46.3–64.4) had confirmed multidrug resistance (MDR). Of our cohort, 91.5% (95% CI: 84.7–95.4) received both BDQ and LZD; the median time on LZD was 8 (IQR: 6–13) weeks. And 76.9% (95% CI: 68.3–83.6) received their complete RR-TB treatment as out-patients.
Table 1. Demographic and Clinical Characteristics of RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019, n = 117
Patients Characteristics n %/Median 95% CI/IQR
Gender
Female 47 40.2 31.6–49.4
Male 70 59.8 50.6–68.4
Median age (IQR) 117 35 27–44
Age group
14–24 22 18.8 12.6–27.0
25–34 33 28.2 20.7–37.2
35–44 34 29.1 21.5–38.0
45–54 17 14.5 9.2–22.3
≥55 11 9.4 5.2–16.3
Previous TB history
New 63 53.8 44.7–62.8
Had DSTB 50 42.7 34.0–52.0
Had DRTB 4 3.4 1.7–8.9
HIV status
Negative 37 31.6 23.7–40.7
Positive 80 68.4 59.3–76.3
ART status during RR-TB Tx (n = 80)
Lost to follow-up 6 7.5 3.3–15.9
Newly diagnosed 12 15.0 8.6–24.8
Stable on antiretroviral 62 77.5 66.8–85.5
Median CD4 at RR-TB initiation (IQR) 76 243 93–459
CD4 at RR-TB initiation (n = 80)
<100 20 25.0 16.6–35.9
100–200 16 20.0 12.5–30.4
200–350 14 17.5 10.5–27.7
≥350 26 32.5 23.0–43.7
CD4 not done 4 5.0 1.8–12.8
RR-TB type
Rif Res on GXP only 39 33.3 25.3–42.5
Rif monoresistance 11 9.4 5.2–16.3
GXP: Rif Res and 1st line LPA sensitive 2 1.7 .4–6.7
Confirmed MDRa 65 55.6 46.3–64.4
Baseline smear results
Negative 63 53.8 44.7–62.8
Positive 52 44.4 35.6–53.7
Test not done 2 1.7 .4–6.7
Baseline culture results
Negative 32 27.4 19.9–36.3
Positive 67 57.3 48.0–66.0
Contaminated 12 10.3 5.9–17.3
Test not done 6 5.1 2.3–11.1
Hb at baseline
<7.9 9 7.7 4.0–14.2
7.9–9.9 26 22.2 15.5–30.8
≥10 82 70.1 61.1–77.8
QTcF at baseline
<450 112 95.7 90.0–98.2
≥450 4 3.4 1.3–8.9
Missing 1 0.9 .1–6.0
Abbreviations: ART, antiretroviral therapy; BDQ, bedaquiline; CI, confidence interval; GXP, GeneXpert (first line test for any presumptive TB case); Hb, hemoglobin; HIV, human immunodeficiency virus; INH, isoniazid; IQR, interquartile range; LPA, line probe assay; MDR, multidrug resistant (resistant to both rifampicin and isoniazid); QTcF, calculated QT interval according to Frederica’s formula; Rif Res, rifampicin resistant; Rif S, rifampicin sensitive; RR-TB, rifampicin-resistant tuberculosis; TB, tuberculosis.
aIsoniazid resistance in these patients was limited to the presence of a single gene mutation (either katG or inhA), because patients with both mutations do not qualify to receive the shorter regimen [7].
Bacteriological Outcomes
Among 117 patients, 44.4% (95% CI: 35.6–53.7) had a positive smear and 57.3% (95% CI: 48.0–66.0) a positive culture at baseline. And 95 patients (81.2%) completed 6 months of treatment and had a median number of monthly follow-up smear and culture results of 6 (IQR 5–6) and 5 (IQR 4–6), respectively (Table 2). Smear conversion was achieved in 92.3% (95% CI: 80.7–97.2), and 7.7% (95% CI: 2.8–19.3) died within 6 months. Culture conversion was achieved in 89.6% (95% CI: 79.3–95.0), 6.0% (95% CI: 2.2–15.2) died, and 4.5% (95% CI: 1.4–13.3) LTFU within 6 months. The median time to smear conversion was 34 days (95% CI: 29–45) and to culture conversion 56 days (95% CI: 50–57) (Figure 3).
Table 2. Smear and Culture Conversion Status at Month 6 for RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019.
Smear and Culture Follow-up and Conversion Status at Month 6 of Treatment n %/Median 95% CI/IQR
Median number of follow-up smears for all 95 6 5–6
Median number of follow-up smears for smear positive at baseline 41 6 5–6
Smear conversion status (n = 52)
Converted negative 48 92.3 80.7–97.2
Died before conversion 4 7.7 2.8–19.3
LTFU before conversion 0 0.0 N/A
Median number of follow-up cultures for all 95 5 4–6
Median number of follow-up cultures for culture positive at baseline 56 5 4–6
Culture conversion status (n = 67)
Converted negative 60 89.6 79.3–95.0
Died before conversion 4 6.0 2.2–15.2
LTFU before conversion 3 4.5 1.4–13.3
Of total cohort (n = 117), 95 completed 6 months treatment. Of 67 culture positive at baseline, 56 completed 6 months treatment. Of 52 smear positive at baseline, 48 completed 6 months treatment.
Abbreviations: BDQ, bedaquiline; CI, confidence interval; IQR, interquartile range; LTFU, lost to follow-up; N/A, not applicable; RR-TB, rifampicin-resistant tuberculosis.
Figure 3. Kaplan-Meier survival estimates for smear/culture positive RR-TB patients at baseline in King Cetshwayo district, 1 July 2018 to 30 April 2019. A, Time to culture conversion (n = 67). B, Time to smear conversion (n = 52). C, Time to culture conversion by HIV status (n = 67); log-rank test within 6 months of follow-up: P = .104. D, Time to culture conversion by CD4 count (n = 45); log-rank test within 3 months of follow-up: P = .826. Abbreviations: HIV, human immunodeficiency virus; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in HIV-negative patients compared to HIV-positive was 90.0% (95% CI: 64.5–97.8) versus 89.4% (95% CI: 76.2–95.7) (P = .938) (Table 3). The median time to culture conversion for HIV-negative and HIV-positive patients was 36 (95% CI: 29–57) and 57 days (95% CI: 53–64), respectively (P = .104) (Figure 3).
Table 3. Culture Conversion Status at Month 6 of Treatment for HIV-positive Patients with Positive Baseline Culture by HIV status and CD4 Cell Count of RR-TB Patients Initiated and Continued on the Short Standardized BDQ-based Regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019
HIV negative (n = 20) HIV positive (n = 45) CD4 <200 cells/µL (n = 20) CD4 ≥200 cells/µL (n = 25)
Culture Conversion Status at Month 6 n % 95% CI n % 95% CI n % 95% CI n % 95% CI
Converted negative 18 90.0 64.5–97.8 42 89.4 76.2–95.7 17 85.0 59.6–95.6 24 96.0 73.7–99.5
Died before conversion 2 10.0 2.2–35.5 2 4.3 1.0–16.2 1 5.0 .5–32.3 1 4.0 .4–26.3
LTFU before conversion 0 0.0 0.0–0.0 3 6.4 2.0–18.7 2 10.0 2.0–35.5 0 0.0 0–0
χ 2 and P value: HIV-negative vs HIV-positive (.006 and .938). CD4 <200 vs ≥200 (1.66 and .198).
Abbreviations: BDQ, bedaquiline; CI, confidence interval; HIV, human immunodeficiency virus; LTFU, lost to follow-up; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in CD4 count <200 cells/µL compared to CD4 count ≥200 cells/µL was 85.0% (95% CI: 59.6–95.6) versus 96.0% (95% CI: 73.7–99.5) (P = .198) (Table 3). We looked at time to culture conversion up to 3 months considering that 3-months culture conversion was known for 82.2% (95% CI: 67.9–92.0) of patients living with HIV with documented baseline CD4. There was no significant difference between KM survival curves of CD4 groups within 3 months of follow-up (P = .826) (Figure 3). The median time to culture conversion within 6 months follow-up in CD4 levels <200 cells/µL was 64 days (95% CI: 32–113) and with CD4 levels ≥200 cells/µL was 57 days (95% CI: 57–68).
Seven patients had a positive culture during their treatment course after achieving culture conversion. Four of the 7 positive cultures occurred after month 6. The positive cultures showed similar resistance patterns to baseline and patients continued the same regimen. All 7 patients reconverted; 5 successfully completed treatment, 1 patient had TMO, and 1 patient was LTFU. Of patients with negative baseline culture samples, 7 developed a positive culture during treatment. Of these 7, 2 patients had culture results with amplified resistance profiles, compared to baseline line probe assay results.
End-of-Treatment Outcomes
Treatment success was achieved in 75.2% (95% CI: 66.5–82.3) of patients. Mortality was 12.8% (95% CI: 7.8–20.3), and 80% (95% CI: 51.9–95.7) of deaths occurred in the first 4 months of treatment. LTFU, treatment failure, and TMO was recorded in 10.3% (95% CI: 5.9–17.3), .9% (95% CI: .01–6.0), and .9% (95% CI: .01–6.0), respectively.
Adverse Events
A total of 298 AEs was recorded; 108 (92.3% [95% CI: 85.8–96.0]) patients experienced at least 1 AE (grade 1–4) during the BDQ course, with a median of 2 (IQR 2–4) AEs per patient. Looking at severe AEs only, a total of 62 severe AEs were recorded in 43 (36.8% [95% CI: 28.4–46.0]) patients. Anemia was the most frequent and accounted for 27 (43.5% [95% CI: 31.0–56.7]) of all severe AEs (Figure 4). For these 27 patients, the median time to severe anemia was 7.1 (IQR 4.0–12.9) weeks after treatment initiation. Of 107 patients who received LZD, 27 (25.2% [95% CI: 17.3–34.6]) developed severe anemia. Of 15 patients who died, severe anemia occurred in 10 (66.7% [95% CI: 38.4–88.2]) patients. In our cohort, grade 3 and 4 QT prolongation occurred in 7 (6.0% [95% CI: 2.4–11.9]) patients. Other severe AEs documented were hepatotoxicity in 9 (14.5% [95% CI: 6.9–25.8]) patients, QT prolongation in 7 (11.3% [95% CI: 4.7–21.9]) patients, nausea and vomiting in 5 (8.1% [95% CI: 2.7–17.8]) patients, and nephrotoxicity in 4 (6.5% [95% CI: 1.8–15.7]) patients. One patient developed optic neuritis and lost all vision. A different patient developed peripheral neuropathy of the lower limbs and fractured her ankle following gait disturbances. These last 2 AEs met the definition of serious AEs.
Figure 4. Frequency of severe AEs experienced in RR-TB patients during first 24 weeks after treatment initiation (N = 62), receiving a short standardized BDQ-based regimen in King Cetshwayo district between 1 July 2018 and 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; RR-TB, rifampicin-resistant tuberculosis.
Management of Adverse Events
Supportive medication was given for symptom control for 103 (34.6% [95% CI: 29.2–40.3]) AEs. No specific management actions were taken for 119 (39.9% [34.3–45.7]) AEs, due to their transient course, clinical insignificance, and/or planned completion of the course of the causative drug. For 21 (7.0% [95% CI: 4.4–10.6]) AEs, patients were hospitalized for further monitoring and treatment.
Hospitalization after treatment initiation occurred in 26 (22.2% [95% CI: 15.1–30.8]) of our patients for various reasons. Among hospitalizations, 18 (69.2% [95% CI: 48.2–85.7]) were attributed to an AE and the need for inpatient management. Of these AE-linked admissions, 8 (44.4% [95% CI: 21.5–69.2]) were due to severe anemia, and 2 (11.1% [95% CI: 1.4–34.7]) were due to a prolonged QT interval.
LZD was interrupted by the provider in 27 (25.2% [95% CI: 17.8–34.5]) participants; the median time on LZD for these patients was 8 (IQR 4–11) weeks. LZD was reintroduced at a reduced dosage of 300 mg/day in 8 occurrences; 1 patient reinitiated the dosage of 600 mg/day; in the remaining 18 cases, LZD was permanently discontinued and not replaced. This was due to various reasons, including receipt of DST results showing an absence of second-line resistance or clinical improvement of the patient on the regimen, where the risks of LZD were felt to outweigh the benefit of continued use. BDQ was interrupted in 3 patients and reinitiated in all, after review and supportive therapy.
DISCUSSION
The South African all-oral short regimen shows good results in a high HIV burden setting. Treatment success was achieved in 75% of our patients, exceeding historical treatment successes of <65% of both the short injectable regimen and the “BLIX” cohort (BDQ and LZD for XDR patients) within the same area [12, 13]. The success rate is similar to that reported from a national cohort in South Africa where BDQ and LZD were combined in a longer regimen [14]. AEs remain common and were often associated with the use of LZD, but some toxicity occurred to other drugs in the regimen. High-dose isoniazid, pyrazinamide, and ethambutol were frequently interrupted following an AE (Figure 5), calling into question the routine use of these drugs for RR-TB treatment, as their effectiveness is also uncertain [6]. Mortality in our cohort remains high, comparable to other oral regimens for RR-TB [14, 16] and happens early during treatment. This can be due to delayed diagnosis and treatment initiation [17]. Most of our patients received their treatment as outpatients, likely reducing costs within a resource-limited healthcare system yet with risk for LTFU, in absence of proper financial and social support.
Figure 5. Graphic illustration of episodes of treatment interruption (N = 94) per individual drug (drug name; n) following an AE in patients during the first 24 weeks of the short standardized BDQ-based regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; CLF, clofazimine; E, ethambutol; ETH, ethionamide; INH hd, high dose isoniazid; LFX, levofloxacin; LZD, linezolid; PZA, pyrazinamide.
Almost 20% of patients initiated on the short regimen were switched to a longer regimen when their baseline resistance profiles became available [7]. We decided not to include these patients in our analysis, as we wanted to assess both tolerability and effectiveness in the “newest” shorter regimen for eligible RR-TB patients. These 30 patients either had isoniazid (INH) mutations and/or levofloxacin or injectable resistance. Although excluded from our analysis, they represent an important population for additional future study, especially to see if the empiric inclusion of LZD as part of the shorter regimen decreases the likelihood of developing resistance to other administered drugs. As patients are currently started on RR-TB treatment before rapid molecular INH and FLQ-resistance results are available, we believe there is benefit in a robust regimen, including LZD, at treatment initiation.
Nearly all of our patients received both BDQ and LZD. The use of these 2 drugs likely contributed to high rates of almost 90% of SC conversion at month 6, exceeding conversion rates in similar settings [18]. LZD has been associated with improved outcomes in RR-TB patients [3, 19] and adding on LZD to the BDQ-based regimen, forming a robust backbone, could have contributed to the rapid time to culture conversion in our cohort. Our results are consistent with those reported under trial conditions, but they are noteworthy, demonstrating what can be achieved in program conditions with high HIV comorbidity [3, 18, 20–25] present. An important finding in our cohort is that HIV status and CD4 levels had no effect on achieving culture conversion, or on time needed to convert within the first 3 months of treatment, even though almost half of our HIV-positive cohort had advanced HIV disease. We acknowledge our small sample size and are cautious drawing conclusions from our findings; nevertheless, this is encouraging for other countries with high HIV/DRTB burden.
Worldwide concern for BDQ-related cardiotoxicity has promoted frequent ECG monitoring [5, 7], yet QT prolongation was observed in <10.0% of the cohort and contributed minimally to hospitalizations. The safety of BDQ has been reinforced in both HIV-negative and HIV-positive patients over the past few years and we see the same reassuring results [20, 26]. LZD-related toxicities, however, remained a challenge, equally noted in other settings [15, 19, 20, 23]. Anemia was the most frequent recorded severe AE, contributing to treatment discontinuation, hospitalization, and possibly mortality within our cohort. Most of the LZD-related toxicities reversed when the drug was discontinued. The overall frequency of peripheral neuropathy in our cohort is low, as LZD exposure was limited to 2 months and possibly underdiagnosis of the pathology. Considering all LZD-associated toxicities, it is crucial to strictly monitor for myelosuppression and neuropathy and to ensure prompt management happens when toxicity occurs [5, 7, 27].
There are several limitations to our analysis. We look at the cohort retrospectively without any comparison group and therefore cannot exclude a general improvement of care contributing to our results. Our cohort was defined as the patients receiving the newly adopted “all-oral BDQ-based” regimen in South Africa, yet the guidance and final recommendation for this regimen was delayed. This led to variable durations of LZD within our cohort. Our data likely underreport on AEs because we relied on routine program data, characterized by inaccuracies in recording. Trained clinicians performed a systematic audit on all clinical charts and missing laboratory results were retrieved online to minimize incompleteness. Retrieving information on AEs a posteriori made it difficult to conduct any causality assessment. We assessed end-of-treatment outcomes with no further follow-up of our cohort and have no data on recurrence rates of this regimen; final outcomes could differ. Fourteen patients had a positive culture, mostly late in treatment, and could be at higher risk for relapse. Long-term follow-up of RR-TB patients completing treatment is necessary to evaluate relapse risk and long-term effectiveness of the shorter regimen.
CONCLUSION
An all-oral shorter regimen, containing BDQ and LZD, shows excellent outcomes in a high HIV prevalent population and used under rural programmatic conditions. The most common AEs were related to LZD, and specific screening and management strategies are needed to identify bone marrow toxicity, especially after the first month of treatment, associated with this medication. In spite of the effectiveness of this regimen, mortality remained high and there is additional support needed to reduce LTFU as well.
South Africa has shown a way for rapid implementation of new regimens under programmatic conditions, using WHO group A drugs to combat their RR-TB epidemic. Given the effectiveness and the feasibility of this regimen, the country can hopefully serve as a model for others to improve RR-TB care for patients worldwide.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ciaa1894_suppl_Supplementary_Material Click here for additional data file.
Notes
Acknowledgments. We would like to acknowledge our patients for their trust in the treating healthcare practitioners, our colleagues from the Department of Health working in RR-TB units implementing new guidelines, and all data encoders at Médecins sans Frontières offices for their work.
Financial support. No external funding was used for this analysis. All work was performed under the usual duties of the Médecins sans Frontières staff.
Potential conflict of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. | BEDAQUILINE, LINEZOLID | DrugsGivenReaction | CC BY-NC-ND | 33372989 | 20,471,125 | 2021-11-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gait disturbance'. | Safety and Effectiveness of an All-Oral, Bedaquiline-Based, Shorter Treatment Regimen for Rifampicin-Resistant Tuberculosis in High Human Immunodeficiency Virus (HIV) Burden Rural South Africa: A Retrospective Cohort Analysis.
At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.
We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database.
Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants.
An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.
pmcRifampicin-resistant tuberculosis (RR-TB) affects over half a million of people each year. South Africa remains among the countries with the highest TB and RR-TB burden in the world, with an estimated incidence of 520 TB cases per 100 000 in 2018, up to 7% of which are rifampicin-resistant [1]. The treatment of RR-TB can be long and complex, associated with toxic agents, yet with treatment success rates remaining at just over 60% [2–4]. New and repurposed drugs are now available, with South Africa rolling out new regimens in recent years. South African programmatic data were used to update the World Health Organization (WHO) recommendations for the treatment of RR-TB in 2018 and 2019. This led to the most recent WHO recommendation for an all-oral shorter regimen in which bedaquiline (BDQ) replaces the injectable [5]. This regimen, however, still includes ethionamide (ETH), a drug with doubtful efficacy, poorly tolerated by patients, and ranked lower than linezolid (LZD) in the WHO RR-TB drug hierarchy. Linezolid, a drug shown to be associated with better outcomes and lower mortality, is currently still excluded from the WHO-recommended shorter regimen [5, 6]. At the end of 2018, South Africa modified its all-oral regimen, recommending 6 months of BDQ and 2 months of LZD for all patients initiating the shorter 9–12 months RR-TB regimen [7]. We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this “newest” treatment regimen under programmatic conditions.
METHODS
Study Design
This is a retrospective cohort analysis of routinely collected programmatic data of RR-TB patients eligible for a short standardized BDQ-based regimen between 1 July 2018 and 30 April 2019 [7]. Study was conducted at 3 RR-TB facilities in King Cetshwayo District, KwaZulu Natal, South Africa.
Study Setting
King Cetshwayo District has a human immunodeficiency virus (HIV) prevalence of 26.4% in the general population and RR-TB rates of 9–12% among all TB cases [8, 9]. In 2011, Médecins sans Frontières (MSF) began working with the National Department of Health (NDoH) and District Health teams to support decentralization of RR-TB care and to improve access to new regimens. Since 2016, RR-TB treatment is provided at 3 ambulatory sites with a centralized in-patient unit if admission is clinically indicated.
RR-TB Treatment Protocol
On diagnosis of rifampicin resistance (by nucleic acid amplification test [GeneXpert; Cepheid] or line probe assay test [GenoType MTBDRplusV2.0; Hain Lifescience]), patients receive clinical evaluation, baseline examinations, and treatment initiation according to NDoH Guidance at a RR-TB treatment site [7]. One sputum sample is collected for smear, culture, and first- and second-line genotypic resistance testing (culture, GenoType MTBDRplus and GenoType MTBDRsl assay are processed by the referral laboratory of the National Health Laboratory Service [NHLS]). This forms the baseline culture for the patient and is taken within the timeframe of 3 months before to 1 month after treatment start.
The South African standard of care for RR-TB changed during 2018. In July, a BDQ-based regimen was implemented. ETH was removed during the following months (some still receiving ETH initially), and it was advised to treat with LZD until second-line resistance could be excluded. This led to variable durations of LZD among patients. In November 2018, a generalized recommendation of 2 months of LZD for all patients initiating RR-TB treatment was released [7] (Figure 2). In patients with hemoglobin levels <8g/dL, LZD initiation is deferred until anemia improves, sometimes requiring blood transfusion.
Figure 2. Diagrammatic overview of the short standardized Bedaquiline-based regimen, indicating recommended duration of each drug as of November 2018 in South Africa (National Department of Health Interim Guidance for the Implementation of Injectable Free Regimens for Rifampicin-Resistant Tuberculosis).
First follow-up of patients happens 2 weeks after initiation. Specific laboratory tests, including full blood and neutrophil count, are recommended, as well as electrocardiogram (ECG) monitoring. Further follow-ups are at week 4 and then monthly, with regular ECG while on BDQ and laboratory tests indicated by the prescribed medications. Monthly bacteriological monitoring consists of both smear and culture (SC) samples for all patients on treatment. Cultures are done by liquid medium (BACTEC MGIT®). Phenotypic drug susceptibility testing (DST) for first- and second-line drugs happens on all positive cultures. Adverse events (AEs) are managed according to their clinical significance and national guidelines [7].
Study Population
We included all RR-TB patients over 18 years of age, eligible for the short standardized all-oral BDQ-based regimen as per NDoH guidance [7], at Eshowe, Mbongolwane, and Catherine Booth hospitals in King Cetshwayo District between 1 July 2018 and 30 April 2019.
Study Variables and Definitions
WHO and national guidelines were used to define RR-TB resistance type and outcome variables such as time to SC conversion, end-of-treatment outcomes, and AEs [7, 10]. Time to SC conversion was defined as the time from initiation of RR-TB treatment to time of SC conversion. SC conversion was reached with 2 consecutive negative SC results on samples collected at least 30 days apart with conversion date being the collection date of the first negative SC sample [10].
End-of-treatment outcomes were assigned by the treating clinician, in line with both NDoH and WHO definitions [7]. An AE is defined as any “untoward medical occurrence in a patient receiving any kind of treatment” [11]. We looked at AEs up until the end of the 24-week BDQ course. AEs are graded on a scale of 1 to 4, with 1 being mild and 4 being life-threatening [11]. AEs of grade 3 and higher are considered severe. AEs occurring more than once in the same patient were recorded by the date of highest severity. AEs leading to persistent disability or hospitalization were noted as serious AEs. It was difficult, however, to conclude occurrence of AEs as causes of death due to incompleteness of AE reporting, to polypharmacy and comorbidities of patients, and unspecified recording on death certificates. QT intervals are calculated according to Frederica’s formula (QTcF) as recommended per national guidelines [7]. Specific cutoff values for numeric variables of laboratory tests to define grading are taken from the Clinical and Programmatic Guide for Patient Management with New TB Drugs (Common Terminology Criteria for Adverse Events [CTCAE] v.4.03 classification) [11]. For the entire cohort, 2 same medical doctors interpreted treating clinicians’ notes for grading of AEs. All pro-formas were checked for completeness by the principal investigator before final recording.
Data Collection and Analysis
Source documents for our study were NDoH Electronic Drug-resistant Tuberculosis Register (EDRWeb), NHLS results, and facility-based clinical charts. Data were extracted by using a standardized data collection tool (see the Supplementary material). All data were entered into an Epi-Info (Centers for Disease Control and Prevention [CDC], Atlanta, GA, USA) database. Continuous variables are presented as medians with interquartile range (IQR). Categorical variables are presented as frequencies and proportions. A χ 2 test was used to compare categorical variables. Time to SC conversion was estimated using Kaplan-Meier (KM) curves. For the analysis of time to SC conversion, the outcome of interest was SC conversion achieved within 3 or 6 months of treatment. If the outcome of interest was not achieved, it was considered as censored.
Censoring occurs when the patient is lost to follow-up (LTFU) or died before achieving SC conversion. The time of censoring was the date of death or LTFU. Censoring also occurred when the patient did not SC convert within 6 months of treatment or transferred or moved out (TMO) before SC conversion was achieved. In our cohort, however, no patient TMO before SC conversion was achieved, and SC conversion status at month 6 was known for all those with positive baseline SC samples. Log-rank test was used to investigate the difference between survival curves. The median time to SC conversion was reported using 95% confidence interval (CI). Data were analyzed using STATA version 15 (StataCorp, College Station, TX, USA).
Ethics
Ethics approval was obtained by MSF Ethics Review Board (Geneva, Switzerland) and the Biomedical Research Ethics Board of the University of KwaZulu-Natal, South Africa.
RESULTS
Patient Characteristics
From 1 July 2018 to 30 April 2019, 194 patients were notified with RR-TB in our district. The short regimen was initiated in 151 patients, yet 19.9% (30/151) were switched to a longer regimen, when their baseline resistance profiles became available, as per NDoH guidelines. Figure 1 shows the patients eligible for the short standardized BDQ-based course included in the final analysis.
Figure 1. Flow diagram of selection of study participants from patients notified with RR-TB in King Cetshwayo district, Kwa-Zulu Natal, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: DR-TB, drug-resistant tuberculosis; INH, isoniazid; RR-TB, rifampicin-resistant tuberculosis.
Table 1 shows the baseline characteristics of these 117 patients. Of our patients, 59.8% (95% CI: 50.6–68.4) were male, 68.4% (95% CI: 59.3–76.3) living with HIV, and 55.6% (95% CI: 46.3–64.4) had confirmed multidrug resistance (MDR). Of our cohort, 91.5% (95% CI: 84.7–95.4) received both BDQ and LZD; the median time on LZD was 8 (IQR: 6–13) weeks. And 76.9% (95% CI: 68.3–83.6) received their complete RR-TB treatment as out-patients.
Table 1. Demographic and Clinical Characteristics of RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019, n = 117
Patients Characteristics n %/Median 95% CI/IQR
Gender
Female 47 40.2 31.6–49.4
Male 70 59.8 50.6–68.4
Median age (IQR) 117 35 27–44
Age group
14–24 22 18.8 12.6–27.0
25–34 33 28.2 20.7–37.2
35–44 34 29.1 21.5–38.0
45–54 17 14.5 9.2–22.3
≥55 11 9.4 5.2–16.3
Previous TB history
New 63 53.8 44.7–62.8
Had DSTB 50 42.7 34.0–52.0
Had DRTB 4 3.4 1.7–8.9
HIV status
Negative 37 31.6 23.7–40.7
Positive 80 68.4 59.3–76.3
ART status during RR-TB Tx (n = 80)
Lost to follow-up 6 7.5 3.3–15.9
Newly diagnosed 12 15.0 8.6–24.8
Stable on antiretroviral 62 77.5 66.8–85.5
Median CD4 at RR-TB initiation (IQR) 76 243 93–459
CD4 at RR-TB initiation (n = 80)
<100 20 25.0 16.6–35.9
100–200 16 20.0 12.5–30.4
200–350 14 17.5 10.5–27.7
≥350 26 32.5 23.0–43.7
CD4 not done 4 5.0 1.8–12.8
RR-TB type
Rif Res on GXP only 39 33.3 25.3–42.5
Rif monoresistance 11 9.4 5.2–16.3
GXP: Rif Res and 1st line LPA sensitive 2 1.7 .4–6.7
Confirmed MDRa 65 55.6 46.3–64.4
Baseline smear results
Negative 63 53.8 44.7–62.8
Positive 52 44.4 35.6–53.7
Test not done 2 1.7 .4–6.7
Baseline culture results
Negative 32 27.4 19.9–36.3
Positive 67 57.3 48.0–66.0
Contaminated 12 10.3 5.9–17.3
Test not done 6 5.1 2.3–11.1
Hb at baseline
<7.9 9 7.7 4.0–14.2
7.9–9.9 26 22.2 15.5–30.8
≥10 82 70.1 61.1–77.8
QTcF at baseline
<450 112 95.7 90.0–98.2
≥450 4 3.4 1.3–8.9
Missing 1 0.9 .1–6.0
Abbreviations: ART, antiretroviral therapy; BDQ, bedaquiline; CI, confidence interval; GXP, GeneXpert (first line test for any presumptive TB case); Hb, hemoglobin; HIV, human immunodeficiency virus; INH, isoniazid; IQR, interquartile range; LPA, line probe assay; MDR, multidrug resistant (resistant to both rifampicin and isoniazid); QTcF, calculated QT interval according to Frederica’s formula; Rif Res, rifampicin resistant; Rif S, rifampicin sensitive; RR-TB, rifampicin-resistant tuberculosis; TB, tuberculosis.
aIsoniazid resistance in these patients was limited to the presence of a single gene mutation (either katG or inhA), because patients with both mutations do not qualify to receive the shorter regimen [7].
Bacteriological Outcomes
Among 117 patients, 44.4% (95% CI: 35.6–53.7) had a positive smear and 57.3% (95% CI: 48.0–66.0) a positive culture at baseline. And 95 patients (81.2%) completed 6 months of treatment and had a median number of monthly follow-up smear and culture results of 6 (IQR 5–6) and 5 (IQR 4–6), respectively (Table 2). Smear conversion was achieved in 92.3% (95% CI: 80.7–97.2), and 7.7% (95% CI: 2.8–19.3) died within 6 months. Culture conversion was achieved in 89.6% (95% CI: 79.3–95.0), 6.0% (95% CI: 2.2–15.2) died, and 4.5% (95% CI: 1.4–13.3) LTFU within 6 months. The median time to smear conversion was 34 days (95% CI: 29–45) and to culture conversion 56 days (95% CI: 50–57) (Figure 3).
Table 2. Smear and Culture Conversion Status at Month 6 for RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019.
Smear and Culture Follow-up and Conversion Status at Month 6 of Treatment n %/Median 95% CI/IQR
Median number of follow-up smears for all 95 6 5–6
Median number of follow-up smears for smear positive at baseline 41 6 5–6
Smear conversion status (n = 52)
Converted negative 48 92.3 80.7–97.2
Died before conversion 4 7.7 2.8–19.3
LTFU before conversion 0 0.0 N/A
Median number of follow-up cultures for all 95 5 4–6
Median number of follow-up cultures for culture positive at baseline 56 5 4–6
Culture conversion status (n = 67)
Converted negative 60 89.6 79.3–95.0
Died before conversion 4 6.0 2.2–15.2
LTFU before conversion 3 4.5 1.4–13.3
Of total cohort (n = 117), 95 completed 6 months treatment. Of 67 culture positive at baseline, 56 completed 6 months treatment. Of 52 smear positive at baseline, 48 completed 6 months treatment.
Abbreviations: BDQ, bedaquiline; CI, confidence interval; IQR, interquartile range; LTFU, lost to follow-up; N/A, not applicable; RR-TB, rifampicin-resistant tuberculosis.
Figure 3. Kaplan-Meier survival estimates for smear/culture positive RR-TB patients at baseline in King Cetshwayo district, 1 July 2018 to 30 April 2019. A, Time to culture conversion (n = 67). B, Time to smear conversion (n = 52). C, Time to culture conversion by HIV status (n = 67); log-rank test within 6 months of follow-up: P = .104. D, Time to culture conversion by CD4 count (n = 45); log-rank test within 3 months of follow-up: P = .826. Abbreviations: HIV, human immunodeficiency virus; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in HIV-negative patients compared to HIV-positive was 90.0% (95% CI: 64.5–97.8) versus 89.4% (95% CI: 76.2–95.7) (P = .938) (Table 3). The median time to culture conversion for HIV-negative and HIV-positive patients was 36 (95% CI: 29–57) and 57 days (95% CI: 53–64), respectively (P = .104) (Figure 3).
Table 3. Culture Conversion Status at Month 6 of Treatment for HIV-positive Patients with Positive Baseline Culture by HIV status and CD4 Cell Count of RR-TB Patients Initiated and Continued on the Short Standardized BDQ-based Regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019
HIV negative (n = 20) HIV positive (n = 45) CD4 <200 cells/µL (n = 20) CD4 ≥200 cells/µL (n = 25)
Culture Conversion Status at Month 6 n % 95% CI n % 95% CI n % 95% CI n % 95% CI
Converted negative 18 90.0 64.5–97.8 42 89.4 76.2–95.7 17 85.0 59.6–95.6 24 96.0 73.7–99.5
Died before conversion 2 10.0 2.2–35.5 2 4.3 1.0–16.2 1 5.0 .5–32.3 1 4.0 .4–26.3
LTFU before conversion 0 0.0 0.0–0.0 3 6.4 2.0–18.7 2 10.0 2.0–35.5 0 0.0 0–0
χ 2 and P value: HIV-negative vs HIV-positive (.006 and .938). CD4 <200 vs ≥200 (1.66 and .198).
Abbreviations: BDQ, bedaquiline; CI, confidence interval; HIV, human immunodeficiency virus; LTFU, lost to follow-up; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in CD4 count <200 cells/µL compared to CD4 count ≥200 cells/µL was 85.0% (95% CI: 59.6–95.6) versus 96.0% (95% CI: 73.7–99.5) (P = .198) (Table 3). We looked at time to culture conversion up to 3 months considering that 3-months culture conversion was known for 82.2% (95% CI: 67.9–92.0) of patients living with HIV with documented baseline CD4. There was no significant difference between KM survival curves of CD4 groups within 3 months of follow-up (P = .826) (Figure 3). The median time to culture conversion within 6 months follow-up in CD4 levels <200 cells/µL was 64 days (95% CI: 32–113) and with CD4 levels ≥200 cells/µL was 57 days (95% CI: 57–68).
Seven patients had a positive culture during their treatment course after achieving culture conversion. Four of the 7 positive cultures occurred after month 6. The positive cultures showed similar resistance patterns to baseline and patients continued the same regimen. All 7 patients reconverted; 5 successfully completed treatment, 1 patient had TMO, and 1 patient was LTFU. Of patients with negative baseline culture samples, 7 developed a positive culture during treatment. Of these 7, 2 patients had culture results with amplified resistance profiles, compared to baseline line probe assay results.
End-of-Treatment Outcomes
Treatment success was achieved in 75.2% (95% CI: 66.5–82.3) of patients. Mortality was 12.8% (95% CI: 7.8–20.3), and 80% (95% CI: 51.9–95.7) of deaths occurred in the first 4 months of treatment. LTFU, treatment failure, and TMO was recorded in 10.3% (95% CI: 5.9–17.3), .9% (95% CI: .01–6.0), and .9% (95% CI: .01–6.0), respectively.
Adverse Events
A total of 298 AEs was recorded; 108 (92.3% [95% CI: 85.8–96.0]) patients experienced at least 1 AE (grade 1–4) during the BDQ course, with a median of 2 (IQR 2–4) AEs per patient. Looking at severe AEs only, a total of 62 severe AEs were recorded in 43 (36.8% [95% CI: 28.4–46.0]) patients. Anemia was the most frequent and accounted for 27 (43.5% [95% CI: 31.0–56.7]) of all severe AEs (Figure 4). For these 27 patients, the median time to severe anemia was 7.1 (IQR 4.0–12.9) weeks after treatment initiation. Of 107 patients who received LZD, 27 (25.2% [95% CI: 17.3–34.6]) developed severe anemia. Of 15 patients who died, severe anemia occurred in 10 (66.7% [95% CI: 38.4–88.2]) patients. In our cohort, grade 3 and 4 QT prolongation occurred in 7 (6.0% [95% CI: 2.4–11.9]) patients. Other severe AEs documented were hepatotoxicity in 9 (14.5% [95% CI: 6.9–25.8]) patients, QT prolongation in 7 (11.3% [95% CI: 4.7–21.9]) patients, nausea and vomiting in 5 (8.1% [95% CI: 2.7–17.8]) patients, and nephrotoxicity in 4 (6.5% [95% CI: 1.8–15.7]) patients. One patient developed optic neuritis and lost all vision. A different patient developed peripheral neuropathy of the lower limbs and fractured her ankle following gait disturbances. These last 2 AEs met the definition of serious AEs.
Figure 4. Frequency of severe AEs experienced in RR-TB patients during first 24 weeks after treatment initiation (N = 62), receiving a short standardized BDQ-based regimen in King Cetshwayo district between 1 July 2018 and 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; RR-TB, rifampicin-resistant tuberculosis.
Management of Adverse Events
Supportive medication was given for symptom control for 103 (34.6% [95% CI: 29.2–40.3]) AEs. No specific management actions were taken for 119 (39.9% [34.3–45.7]) AEs, due to their transient course, clinical insignificance, and/or planned completion of the course of the causative drug. For 21 (7.0% [95% CI: 4.4–10.6]) AEs, patients were hospitalized for further monitoring and treatment.
Hospitalization after treatment initiation occurred in 26 (22.2% [95% CI: 15.1–30.8]) of our patients for various reasons. Among hospitalizations, 18 (69.2% [95% CI: 48.2–85.7]) were attributed to an AE and the need for inpatient management. Of these AE-linked admissions, 8 (44.4% [95% CI: 21.5–69.2]) were due to severe anemia, and 2 (11.1% [95% CI: 1.4–34.7]) were due to a prolonged QT interval.
LZD was interrupted by the provider in 27 (25.2% [95% CI: 17.8–34.5]) participants; the median time on LZD for these patients was 8 (IQR 4–11) weeks. LZD was reintroduced at a reduced dosage of 300 mg/day in 8 occurrences; 1 patient reinitiated the dosage of 600 mg/day; in the remaining 18 cases, LZD was permanently discontinued and not replaced. This was due to various reasons, including receipt of DST results showing an absence of second-line resistance or clinical improvement of the patient on the regimen, where the risks of LZD were felt to outweigh the benefit of continued use. BDQ was interrupted in 3 patients and reinitiated in all, after review and supportive therapy.
DISCUSSION
The South African all-oral short regimen shows good results in a high HIV burden setting. Treatment success was achieved in 75% of our patients, exceeding historical treatment successes of <65% of both the short injectable regimen and the “BLIX” cohort (BDQ and LZD for XDR patients) within the same area [12, 13]. The success rate is similar to that reported from a national cohort in South Africa where BDQ and LZD were combined in a longer regimen [14]. AEs remain common and were often associated with the use of LZD, but some toxicity occurred to other drugs in the regimen. High-dose isoniazid, pyrazinamide, and ethambutol were frequently interrupted following an AE (Figure 5), calling into question the routine use of these drugs for RR-TB treatment, as their effectiveness is also uncertain [6]. Mortality in our cohort remains high, comparable to other oral regimens for RR-TB [14, 16] and happens early during treatment. This can be due to delayed diagnosis and treatment initiation [17]. Most of our patients received their treatment as outpatients, likely reducing costs within a resource-limited healthcare system yet with risk for LTFU, in absence of proper financial and social support.
Figure 5. Graphic illustration of episodes of treatment interruption (N = 94) per individual drug (drug name; n) following an AE in patients during the first 24 weeks of the short standardized BDQ-based regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; CLF, clofazimine; E, ethambutol; ETH, ethionamide; INH hd, high dose isoniazid; LFX, levofloxacin; LZD, linezolid; PZA, pyrazinamide.
Almost 20% of patients initiated on the short regimen were switched to a longer regimen when their baseline resistance profiles became available [7]. We decided not to include these patients in our analysis, as we wanted to assess both tolerability and effectiveness in the “newest” shorter regimen for eligible RR-TB patients. These 30 patients either had isoniazid (INH) mutations and/or levofloxacin or injectable resistance. Although excluded from our analysis, they represent an important population for additional future study, especially to see if the empiric inclusion of LZD as part of the shorter regimen decreases the likelihood of developing resistance to other administered drugs. As patients are currently started on RR-TB treatment before rapid molecular INH and FLQ-resistance results are available, we believe there is benefit in a robust regimen, including LZD, at treatment initiation.
Nearly all of our patients received both BDQ and LZD. The use of these 2 drugs likely contributed to high rates of almost 90% of SC conversion at month 6, exceeding conversion rates in similar settings [18]. LZD has been associated with improved outcomes in RR-TB patients [3, 19] and adding on LZD to the BDQ-based regimen, forming a robust backbone, could have contributed to the rapid time to culture conversion in our cohort. Our results are consistent with those reported under trial conditions, but they are noteworthy, demonstrating what can be achieved in program conditions with high HIV comorbidity [3, 18, 20–25] present. An important finding in our cohort is that HIV status and CD4 levels had no effect on achieving culture conversion, or on time needed to convert within the first 3 months of treatment, even though almost half of our HIV-positive cohort had advanced HIV disease. We acknowledge our small sample size and are cautious drawing conclusions from our findings; nevertheless, this is encouraging for other countries with high HIV/DRTB burden.
Worldwide concern for BDQ-related cardiotoxicity has promoted frequent ECG monitoring [5, 7], yet QT prolongation was observed in <10.0% of the cohort and contributed minimally to hospitalizations. The safety of BDQ has been reinforced in both HIV-negative and HIV-positive patients over the past few years and we see the same reassuring results [20, 26]. LZD-related toxicities, however, remained a challenge, equally noted in other settings [15, 19, 20, 23]. Anemia was the most frequent recorded severe AE, contributing to treatment discontinuation, hospitalization, and possibly mortality within our cohort. Most of the LZD-related toxicities reversed when the drug was discontinued. The overall frequency of peripheral neuropathy in our cohort is low, as LZD exposure was limited to 2 months and possibly underdiagnosis of the pathology. Considering all LZD-associated toxicities, it is crucial to strictly monitor for myelosuppression and neuropathy and to ensure prompt management happens when toxicity occurs [5, 7, 27].
There are several limitations to our analysis. We look at the cohort retrospectively without any comparison group and therefore cannot exclude a general improvement of care contributing to our results. Our cohort was defined as the patients receiving the newly adopted “all-oral BDQ-based” regimen in South Africa, yet the guidance and final recommendation for this regimen was delayed. This led to variable durations of LZD within our cohort. Our data likely underreport on AEs because we relied on routine program data, characterized by inaccuracies in recording. Trained clinicians performed a systematic audit on all clinical charts and missing laboratory results were retrieved online to minimize incompleteness. Retrieving information on AEs a posteriori made it difficult to conduct any causality assessment. We assessed end-of-treatment outcomes with no further follow-up of our cohort and have no data on recurrence rates of this regimen; final outcomes could differ. Fourteen patients had a positive culture, mostly late in treatment, and could be at higher risk for relapse. Long-term follow-up of RR-TB patients completing treatment is necessary to evaluate relapse risk and long-term effectiveness of the shorter regimen.
CONCLUSION
An all-oral shorter regimen, containing BDQ and LZD, shows excellent outcomes in a high HIV prevalent population and used under rural programmatic conditions. The most common AEs were related to LZD, and specific screening and management strategies are needed to identify bone marrow toxicity, especially after the first month of treatment, associated with this medication. In spite of the effectiveness of this regimen, mortality remained high and there is additional support needed to reduce LTFU as well.
South Africa has shown a way for rapid implementation of new regimens under programmatic conditions, using WHO group A drugs to combat their RR-TB epidemic. Given the effectiveness and the feasibility of this regimen, the country can hopefully serve as a model for others to improve RR-TB care for patients worldwide.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ciaa1894_suppl_Supplementary_Material Click here for additional data file.
Notes
Acknowledgments. We would like to acknowledge our patients for their trust in the treating healthcare practitioners, our colleagues from the Department of Health working in RR-TB units implementing new guidelines, and all data encoders at Médecins sans Frontières offices for their work.
Financial support. No external funding was used for this analysis. All work was performed under the usual duties of the Médecins sans Frontières staff.
Potential conflict of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. | BEDAQUILINE, LINEZOLID | DrugsGivenReaction | CC BY-NC-ND | 33372989 | 20,471,124 | 2021-11-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuropathy peripheral'. | Safety and Effectiveness of an All-Oral, Bedaquiline-Based, Shorter Treatment Regimen for Rifampicin-Resistant Tuberculosis in High Human Immunodeficiency Virus (HIV) Burden Rural South Africa: A Retrospective Cohort Analysis.
At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.
We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database.
Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants.
An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.
pmcRifampicin-resistant tuberculosis (RR-TB) affects over half a million of people each year. South Africa remains among the countries with the highest TB and RR-TB burden in the world, with an estimated incidence of 520 TB cases per 100 000 in 2018, up to 7% of which are rifampicin-resistant [1]. The treatment of RR-TB can be long and complex, associated with toxic agents, yet with treatment success rates remaining at just over 60% [2–4]. New and repurposed drugs are now available, with South Africa rolling out new regimens in recent years. South African programmatic data were used to update the World Health Organization (WHO) recommendations for the treatment of RR-TB in 2018 and 2019. This led to the most recent WHO recommendation for an all-oral shorter regimen in which bedaquiline (BDQ) replaces the injectable [5]. This regimen, however, still includes ethionamide (ETH), a drug with doubtful efficacy, poorly tolerated by patients, and ranked lower than linezolid (LZD) in the WHO RR-TB drug hierarchy. Linezolid, a drug shown to be associated with better outcomes and lower mortality, is currently still excluded from the WHO-recommended shorter regimen [5, 6]. At the end of 2018, South Africa modified its all-oral regimen, recommending 6 months of BDQ and 2 months of LZD for all patients initiating the shorter 9–12 months RR-TB regimen [7]. We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this “newest” treatment regimen under programmatic conditions.
METHODS
Study Design
This is a retrospective cohort analysis of routinely collected programmatic data of RR-TB patients eligible for a short standardized BDQ-based regimen between 1 July 2018 and 30 April 2019 [7]. Study was conducted at 3 RR-TB facilities in King Cetshwayo District, KwaZulu Natal, South Africa.
Study Setting
King Cetshwayo District has a human immunodeficiency virus (HIV) prevalence of 26.4% in the general population and RR-TB rates of 9–12% among all TB cases [8, 9]. In 2011, Médecins sans Frontières (MSF) began working with the National Department of Health (NDoH) and District Health teams to support decentralization of RR-TB care and to improve access to new regimens. Since 2016, RR-TB treatment is provided at 3 ambulatory sites with a centralized in-patient unit if admission is clinically indicated.
RR-TB Treatment Protocol
On diagnosis of rifampicin resistance (by nucleic acid amplification test [GeneXpert; Cepheid] or line probe assay test [GenoType MTBDRplusV2.0; Hain Lifescience]), patients receive clinical evaluation, baseline examinations, and treatment initiation according to NDoH Guidance at a RR-TB treatment site [7]. One sputum sample is collected for smear, culture, and first- and second-line genotypic resistance testing (culture, GenoType MTBDRplus and GenoType MTBDRsl assay are processed by the referral laboratory of the National Health Laboratory Service [NHLS]). This forms the baseline culture for the patient and is taken within the timeframe of 3 months before to 1 month after treatment start.
The South African standard of care for RR-TB changed during 2018. In July, a BDQ-based regimen was implemented. ETH was removed during the following months (some still receiving ETH initially), and it was advised to treat with LZD until second-line resistance could be excluded. This led to variable durations of LZD among patients. In November 2018, a generalized recommendation of 2 months of LZD for all patients initiating RR-TB treatment was released [7] (Figure 2). In patients with hemoglobin levels <8g/dL, LZD initiation is deferred until anemia improves, sometimes requiring blood transfusion.
Figure 2. Diagrammatic overview of the short standardized Bedaquiline-based regimen, indicating recommended duration of each drug as of November 2018 in South Africa (National Department of Health Interim Guidance for the Implementation of Injectable Free Regimens for Rifampicin-Resistant Tuberculosis).
First follow-up of patients happens 2 weeks after initiation. Specific laboratory tests, including full blood and neutrophil count, are recommended, as well as electrocardiogram (ECG) monitoring. Further follow-ups are at week 4 and then monthly, with regular ECG while on BDQ and laboratory tests indicated by the prescribed medications. Monthly bacteriological monitoring consists of both smear and culture (SC) samples for all patients on treatment. Cultures are done by liquid medium (BACTEC MGIT®). Phenotypic drug susceptibility testing (DST) for first- and second-line drugs happens on all positive cultures. Adverse events (AEs) are managed according to their clinical significance and national guidelines [7].
Study Population
We included all RR-TB patients over 18 years of age, eligible for the short standardized all-oral BDQ-based regimen as per NDoH guidance [7], at Eshowe, Mbongolwane, and Catherine Booth hospitals in King Cetshwayo District between 1 July 2018 and 30 April 2019.
Study Variables and Definitions
WHO and national guidelines were used to define RR-TB resistance type and outcome variables such as time to SC conversion, end-of-treatment outcomes, and AEs [7, 10]. Time to SC conversion was defined as the time from initiation of RR-TB treatment to time of SC conversion. SC conversion was reached with 2 consecutive negative SC results on samples collected at least 30 days apart with conversion date being the collection date of the first negative SC sample [10].
End-of-treatment outcomes were assigned by the treating clinician, in line with both NDoH and WHO definitions [7]. An AE is defined as any “untoward medical occurrence in a patient receiving any kind of treatment” [11]. We looked at AEs up until the end of the 24-week BDQ course. AEs are graded on a scale of 1 to 4, with 1 being mild and 4 being life-threatening [11]. AEs of grade 3 and higher are considered severe. AEs occurring more than once in the same patient were recorded by the date of highest severity. AEs leading to persistent disability or hospitalization were noted as serious AEs. It was difficult, however, to conclude occurrence of AEs as causes of death due to incompleteness of AE reporting, to polypharmacy and comorbidities of patients, and unspecified recording on death certificates. QT intervals are calculated according to Frederica’s formula (QTcF) as recommended per national guidelines [7]. Specific cutoff values for numeric variables of laboratory tests to define grading are taken from the Clinical and Programmatic Guide for Patient Management with New TB Drugs (Common Terminology Criteria for Adverse Events [CTCAE] v.4.03 classification) [11]. For the entire cohort, 2 same medical doctors interpreted treating clinicians’ notes for grading of AEs. All pro-formas were checked for completeness by the principal investigator before final recording.
Data Collection and Analysis
Source documents for our study were NDoH Electronic Drug-resistant Tuberculosis Register (EDRWeb), NHLS results, and facility-based clinical charts. Data were extracted by using a standardized data collection tool (see the Supplementary material). All data were entered into an Epi-Info (Centers for Disease Control and Prevention [CDC], Atlanta, GA, USA) database. Continuous variables are presented as medians with interquartile range (IQR). Categorical variables are presented as frequencies and proportions. A χ 2 test was used to compare categorical variables. Time to SC conversion was estimated using Kaplan-Meier (KM) curves. For the analysis of time to SC conversion, the outcome of interest was SC conversion achieved within 3 or 6 months of treatment. If the outcome of interest was not achieved, it was considered as censored.
Censoring occurs when the patient is lost to follow-up (LTFU) or died before achieving SC conversion. The time of censoring was the date of death or LTFU. Censoring also occurred when the patient did not SC convert within 6 months of treatment or transferred or moved out (TMO) before SC conversion was achieved. In our cohort, however, no patient TMO before SC conversion was achieved, and SC conversion status at month 6 was known for all those with positive baseline SC samples. Log-rank test was used to investigate the difference between survival curves. The median time to SC conversion was reported using 95% confidence interval (CI). Data were analyzed using STATA version 15 (StataCorp, College Station, TX, USA).
Ethics
Ethics approval was obtained by MSF Ethics Review Board (Geneva, Switzerland) and the Biomedical Research Ethics Board of the University of KwaZulu-Natal, South Africa.
RESULTS
Patient Characteristics
From 1 July 2018 to 30 April 2019, 194 patients were notified with RR-TB in our district. The short regimen was initiated in 151 patients, yet 19.9% (30/151) were switched to a longer regimen, when their baseline resistance profiles became available, as per NDoH guidelines. Figure 1 shows the patients eligible for the short standardized BDQ-based course included in the final analysis.
Figure 1. Flow diagram of selection of study participants from patients notified with RR-TB in King Cetshwayo district, Kwa-Zulu Natal, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: DR-TB, drug-resistant tuberculosis; INH, isoniazid; RR-TB, rifampicin-resistant tuberculosis.
Table 1 shows the baseline characteristics of these 117 patients. Of our patients, 59.8% (95% CI: 50.6–68.4) were male, 68.4% (95% CI: 59.3–76.3) living with HIV, and 55.6% (95% CI: 46.3–64.4) had confirmed multidrug resistance (MDR). Of our cohort, 91.5% (95% CI: 84.7–95.4) received both BDQ and LZD; the median time on LZD was 8 (IQR: 6–13) weeks. And 76.9% (95% CI: 68.3–83.6) received their complete RR-TB treatment as out-patients.
Table 1. Demographic and Clinical Characteristics of RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019, n = 117
Patients Characteristics n %/Median 95% CI/IQR
Gender
Female 47 40.2 31.6–49.4
Male 70 59.8 50.6–68.4
Median age (IQR) 117 35 27–44
Age group
14–24 22 18.8 12.6–27.0
25–34 33 28.2 20.7–37.2
35–44 34 29.1 21.5–38.0
45–54 17 14.5 9.2–22.3
≥55 11 9.4 5.2–16.3
Previous TB history
New 63 53.8 44.7–62.8
Had DSTB 50 42.7 34.0–52.0
Had DRTB 4 3.4 1.7–8.9
HIV status
Negative 37 31.6 23.7–40.7
Positive 80 68.4 59.3–76.3
ART status during RR-TB Tx (n = 80)
Lost to follow-up 6 7.5 3.3–15.9
Newly diagnosed 12 15.0 8.6–24.8
Stable on antiretroviral 62 77.5 66.8–85.5
Median CD4 at RR-TB initiation (IQR) 76 243 93–459
CD4 at RR-TB initiation (n = 80)
<100 20 25.0 16.6–35.9
100–200 16 20.0 12.5–30.4
200–350 14 17.5 10.5–27.7
≥350 26 32.5 23.0–43.7
CD4 not done 4 5.0 1.8–12.8
RR-TB type
Rif Res on GXP only 39 33.3 25.3–42.5
Rif monoresistance 11 9.4 5.2–16.3
GXP: Rif Res and 1st line LPA sensitive 2 1.7 .4–6.7
Confirmed MDRa 65 55.6 46.3–64.4
Baseline smear results
Negative 63 53.8 44.7–62.8
Positive 52 44.4 35.6–53.7
Test not done 2 1.7 .4–6.7
Baseline culture results
Negative 32 27.4 19.9–36.3
Positive 67 57.3 48.0–66.0
Contaminated 12 10.3 5.9–17.3
Test not done 6 5.1 2.3–11.1
Hb at baseline
<7.9 9 7.7 4.0–14.2
7.9–9.9 26 22.2 15.5–30.8
≥10 82 70.1 61.1–77.8
QTcF at baseline
<450 112 95.7 90.0–98.2
≥450 4 3.4 1.3–8.9
Missing 1 0.9 .1–6.0
Abbreviations: ART, antiretroviral therapy; BDQ, bedaquiline; CI, confidence interval; GXP, GeneXpert (first line test for any presumptive TB case); Hb, hemoglobin; HIV, human immunodeficiency virus; INH, isoniazid; IQR, interquartile range; LPA, line probe assay; MDR, multidrug resistant (resistant to both rifampicin and isoniazid); QTcF, calculated QT interval according to Frederica’s formula; Rif Res, rifampicin resistant; Rif S, rifampicin sensitive; RR-TB, rifampicin-resistant tuberculosis; TB, tuberculosis.
aIsoniazid resistance in these patients was limited to the presence of a single gene mutation (either katG or inhA), because patients with both mutations do not qualify to receive the shorter regimen [7].
Bacteriological Outcomes
Among 117 patients, 44.4% (95% CI: 35.6–53.7) had a positive smear and 57.3% (95% CI: 48.0–66.0) a positive culture at baseline. And 95 patients (81.2%) completed 6 months of treatment and had a median number of monthly follow-up smear and culture results of 6 (IQR 5–6) and 5 (IQR 4–6), respectively (Table 2). Smear conversion was achieved in 92.3% (95% CI: 80.7–97.2), and 7.7% (95% CI: 2.8–19.3) died within 6 months. Culture conversion was achieved in 89.6% (95% CI: 79.3–95.0), 6.0% (95% CI: 2.2–15.2) died, and 4.5% (95% CI: 1.4–13.3) LTFU within 6 months. The median time to smear conversion was 34 days (95% CI: 29–45) and to culture conversion 56 days (95% CI: 50–57) (Figure 3).
Table 2. Smear and Culture Conversion Status at Month 6 for RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019.
Smear and Culture Follow-up and Conversion Status at Month 6 of Treatment n %/Median 95% CI/IQR
Median number of follow-up smears for all 95 6 5–6
Median number of follow-up smears for smear positive at baseline 41 6 5–6
Smear conversion status (n = 52)
Converted negative 48 92.3 80.7–97.2
Died before conversion 4 7.7 2.8–19.3
LTFU before conversion 0 0.0 N/A
Median number of follow-up cultures for all 95 5 4–6
Median number of follow-up cultures for culture positive at baseline 56 5 4–6
Culture conversion status (n = 67)
Converted negative 60 89.6 79.3–95.0
Died before conversion 4 6.0 2.2–15.2
LTFU before conversion 3 4.5 1.4–13.3
Of total cohort (n = 117), 95 completed 6 months treatment. Of 67 culture positive at baseline, 56 completed 6 months treatment. Of 52 smear positive at baseline, 48 completed 6 months treatment.
Abbreviations: BDQ, bedaquiline; CI, confidence interval; IQR, interquartile range; LTFU, lost to follow-up; N/A, not applicable; RR-TB, rifampicin-resistant tuberculosis.
Figure 3. Kaplan-Meier survival estimates for smear/culture positive RR-TB patients at baseline in King Cetshwayo district, 1 July 2018 to 30 April 2019. A, Time to culture conversion (n = 67). B, Time to smear conversion (n = 52). C, Time to culture conversion by HIV status (n = 67); log-rank test within 6 months of follow-up: P = .104. D, Time to culture conversion by CD4 count (n = 45); log-rank test within 3 months of follow-up: P = .826. Abbreviations: HIV, human immunodeficiency virus; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in HIV-negative patients compared to HIV-positive was 90.0% (95% CI: 64.5–97.8) versus 89.4% (95% CI: 76.2–95.7) (P = .938) (Table 3). The median time to culture conversion for HIV-negative and HIV-positive patients was 36 (95% CI: 29–57) and 57 days (95% CI: 53–64), respectively (P = .104) (Figure 3).
Table 3. Culture Conversion Status at Month 6 of Treatment for HIV-positive Patients with Positive Baseline Culture by HIV status and CD4 Cell Count of RR-TB Patients Initiated and Continued on the Short Standardized BDQ-based Regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019
HIV negative (n = 20) HIV positive (n = 45) CD4 <200 cells/µL (n = 20) CD4 ≥200 cells/µL (n = 25)
Culture Conversion Status at Month 6 n % 95% CI n % 95% CI n % 95% CI n % 95% CI
Converted negative 18 90.0 64.5–97.8 42 89.4 76.2–95.7 17 85.0 59.6–95.6 24 96.0 73.7–99.5
Died before conversion 2 10.0 2.2–35.5 2 4.3 1.0–16.2 1 5.0 .5–32.3 1 4.0 .4–26.3
LTFU before conversion 0 0.0 0.0–0.0 3 6.4 2.0–18.7 2 10.0 2.0–35.5 0 0.0 0–0
χ 2 and P value: HIV-negative vs HIV-positive (.006 and .938). CD4 <200 vs ≥200 (1.66 and .198).
Abbreviations: BDQ, bedaquiline; CI, confidence interval; HIV, human immunodeficiency virus; LTFU, lost to follow-up; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in CD4 count <200 cells/µL compared to CD4 count ≥200 cells/µL was 85.0% (95% CI: 59.6–95.6) versus 96.0% (95% CI: 73.7–99.5) (P = .198) (Table 3). We looked at time to culture conversion up to 3 months considering that 3-months culture conversion was known for 82.2% (95% CI: 67.9–92.0) of patients living with HIV with documented baseline CD4. There was no significant difference between KM survival curves of CD4 groups within 3 months of follow-up (P = .826) (Figure 3). The median time to culture conversion within 6 months follow-up in CD4 levels <200 cells/µL was 64 days (95% CI: 32–113) and with CD4 levels ≥200 cells/µL was 57 days (95% CI: 57–68).
Seven patients had a positive culture during their treatment course after achieving culture conversion. Four of the 7 positive cultures occurred after month 6. The positive cultures showed similar resistance patterns to baseline and patients continued the same regimen. All 7 patients reconverted; 5 successfully completed treatment, 1 patient had TMO, and 1 patient was LTFU. Of patients with negative baseline culture samples, 7 developed a positive culture during treatment. Of these 7, 2 patients had culture results with amplified resistance profiles, compared to baseline line probe assay results.
End-of-Treatment Outcomes
Treatment success was achieved in 75.2% (95% CI: 66.5–82.3) of patients. Mortality was 12.8% (95% CI: 7.8–20.3), and 80% (95% CI: 51.9–95.7) of deaths occurred in the first 4 months of treatment. LTFU, treatment failure, and TMO was recorded in 10.3% (95% CI: 5.9–17.3), .9% (95% CI: .01–6.0), and .9% (95% CI: .01–6.0), respectively.
Adverse Events
A total of 298 AEs was recorded; 108 (92.3% [95% CI: 85.8–96.0]) patients experienced at least 1 AE (grade 1–4) during the BDQ course, with a median of 2 (IQR 2–4) AEs per patient. Looking at severe AEs only, a total of 62 severe AEs were recorded in 43 (36.8% [95% CI: 28.4–46.0]) patients. Anemia was the most frequent and accounted for 27 (43.5% [95% CI: 31.0–56.7]) of all severe AEs (Figure 4). For these 27 patients, the median time to severe anemia was 7.1 (IQR 4.0–12.9) weeks after treatment initiation. Of 107 patients who received LZD, 27 (25.2% [95% CI: 17.3–34.6]) developed severe anemia. Of 15 patients who died, severe anemia occurred in 10 (66.7% [95% CI: 38.4–88.2]) patients. In our cohort, grade 3 and 4 QT prolongation occurred in 7 (6.0% [95% CI: 2.4–11.9]) patients. Other severe AEs documented were hepatotoxicity in 9 (14.5% [95% CI: 6.9–25.8]) patients, QT prolongation in 7 (11.3% [95% CI: 4.7–21.9]) patients, nausea and vomiting in 5 (8.1% [95% CI: 2.7–17.8]) patients, and nephrotoxicity in 4 (6.5% [95% CI: 1.8–15.7]) patients. One patient developed optic neuritis and lost all vision. A different patient developed peripheral neuropathy of the lower limbs and fractured her ankle following gait disturbances. These last 2 AEs met the definition of serious AEs.
Figure 4. Frequency of severe AEs experienced in RR-TB patients during first 24 weeks after treatment initiation (N = 62), receiving a short standardized BDQ-based regimen in King Cetshwayo district between 1 July 2018 and 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; RR-TB, rifampicin-resistant tuberculosis.
Management of Adverse Events
Supportive medication was given for symptom control for 103 (34.6% [95% CI: 29.2–40.3]) AEs. No specific management actions were taken for 119 (39.9% [34.3–45.7]) AEs, due to their transient course, clinical insignificance, and/or planned completion of the course of the causative drug. For 21 (7.0% [95% CI: 4.4–10.6]) AEs, patients were hospitalized for further monitoring and treatment.
Hospitalization after treatment initiation occurred in 26 (22.2% [95% CI: 15.1–30.8]) of our patients for various reasons. Among hospitalizations, 18 (69.2% [95% CI: 48.2–85.7]) were attributed to an AE and the need for inpatient management. Of these AE-linked admissions, 8 (44.4% [95% CI: 21.5–69.2]) were due to severe anemia, and 2 (11.1% [95% CI: 1.4–34.7]) were due to a prolonged QT interval.
LZD was interrupted by the provider in 27 (25.2% [95% CI: 17.8–34.5]) participants; the median time on LZD for these patients was 8 (IQR 4–11) weeks. LZD was reintroduced at a reduced dosage of 300 mg/day in 8 occurrences; 1 patient reinitiated the dosage of 600 mg/day; in the remaining 18 cases, LZD was permanently discontinued and not replaced. This was due to various reasons, including receipt of DST results showing an absence of second-line resistance or clinical improvement of the patient on the regimen, where the risks of LZD were felt to outweigh the benefit of continued use. BDQ was interrupted in 3 patients and reinitiated in all, after review and supportive therapy.
DISCUSSION
The South African all-oral short regimen shows good results in a high HIV burden setting. Treatment success was achieved in 75% of our patients, exceeding historical treatment successes of <65% of both the short injectable regimen and the “BLIX” cohort (BDQ and LZD for XDR patients) within the same area [12, 13]. The success rate is similar to that reported from a national cohort in South Africa where BDQ and LZD were combined in a longer regimen [14]. AEs remain common and were often associated with the use of LZD, but some toxicity occurred to other drugs in the regimen. High-dose isoniazid, pyrazinamide, and ethambutol were frequently interrupted following an AE (Figure 5), calling into question the routine use of these drugs for RR-TB treatment, as their effectiveness is also uncertain [6]. Mortality in our cohort remains high, comparable to other oral regimens for RR-TB [14, 16] and happens early during treatment. This can be due to delayed diagnosis and treatment initiation [17]. Most of our patients received their treatment as outpatients, likely reducing costs within a resource-limited healthcare system yet with risk for LTFU, in absence of proper financial and social support.
Figure 5. Graphic illustration of episodes of treatment interruption (N = 94) per individual drug (drug name; n) following an AE in patients during the first 24 weeks of the short standardized BDQ-based regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; CLF, clofazimine; E, ethambutol; ETH, ethionamide; INH hd, high dose isoniazid; LFX, levofloxacin; LZD, linezolid; PZA, pyrazinamide.
Almost 20% of patients initiated on the short regimen were switched to a longer regimen when their baseline resistance profiles became available [7]. We decided not to include these patients in our analysis, as we wanted to assess both tolerability and effectiveness in the “newest” shorter regimen for eligible RR-TB patients. These 30 patients either had isoniazid (INH) mutations and/or levofloxacin or injectable resistance. Although excluded from our analysis, they represent an important population for additional future study, especially to see if the empiric inclusion of LZD as part of the shorter regimen decreases the likelihood of developing resistance to other administered drugs. As patients are currently started on RR-TB treatment before rapid molecular INH and FLQ-resistance results are available, we believe there is benefit in a robust regimen, including LZD, at treatment initiation.
Nearly all of our patients received both BDQ and LZD. The use of these 2 drugs likely contributed to high rates of almost 90% of SC conversion at month 6, exceeding conversion rates in similar settings [18]. LZD has been associated with improved outcomes in RR-TB patients [3, 19] and adding on LZD to the BDQ-based regimen, forming a robust backbone, could have contributed to the rapid time to culture conversion in our cohort. Our results are consistent with those reported under trial conditions, but they are noteworthy, demonstrating what can be achieved in program conditions with high HIV comorbidity [3, 18, 20–25] present. An important finding in our cohort is that HIV status and CD4 levels had no effect on achieving culture conversion, or on time needed to convert within the first 3 months of treatment, even though almost half of our HIV-positive cohort had advanced HIV disease. We acknowledge our small sample size and are cautious drawing conclusions from our findings; nevertheless, this is encouraging for other countries with high HIV/DRTB burden.
Worldwide concern for BDQ-related cardiotoxicity has promoted frequent ECG monitoring [5, 7], yet QT prolongation was observed in <10.0% of the cohort and contributed minimally to hospitalizations. The safety of BDQ has been reinforced in both HIV-negative and HIV-positive patients over the past few years and we see the same reassuring results [20, 26]. LZD-related toxicities, however, remained a challenge, equally noted in other settings [15, 19, 20, 23]. Anemia was the most frequent recorded severe AE, contributing to treatment discontinuation, hospitalization, and possibly mortality within our cohort. Most of the LZD-related toxicities reversed when the drug was discontinued. The overall frequency of peripheral neuropathy in our cohort is low, as LZD exposure was limited to 2 months and possibly underdiagnosis of the pathology. Considering all LZD-associated toxicities, it is crucial to strictly monitor for myelosuppression and neuropathy and to ensure prompt management happens when toxicity occurs [5, 7, 27].
There are several limitations to our analysis. We look at the cohort retrospectively without any comparison group and therefore cannot exclude a general improvement of care contributing to our results. Our cohort was defined as the patients receiving the newly adopted “all-oral BDQ-based” regimen in South Africa, yet the guidance and final recommendation for this regimen was delayed. This led to variable durations of LZD within our cohort. Our data likely underreport on AEs because we relied on routine program data, characterized by inaccuracies in recording. Trained clinicians performed a systematic audit on all clinical charts and missing laboratory results were retrieved online to minimize incompleteness. Retrieving information on AEs a posteriori made it difficult to conduct any causality assessment. We assessed end-of-treatment outcomes with no further follow-up of our cohort and have no data on recurrence rates of this regimen; final outcomes could differ. Fourteen patients had a positive culture, mostly late in treatment, and could be at higher risk for relapse. Long-term follow-up of RR-TB patients completing treatment is necessary to evaluate relapse risk and long-term effectiveness of the shorter regimen.
CONCLUSION
An all-oral shorter regimen, containing BDQ and LZD, shows excellent outcomes in a high HIV prevalent population and used under rural programmatic conditions. The most common AEs were related to LZD, and specific screening and management strategies are needed to identify bone marrow toxicity, especially after the first month of treatment, associated with this medication. In spite of the effectiveness of this regimen, mortality remained high and there is additional support needed to reduce LTFU as well.
South Africa has shown a way for rapid implementation of new regimens under programmatic conditions, using WHO group A drugs to combat their RR-TB epidemic. Given the effectiveness and the feasibility of this regimen, the country can hopefully serve as a model for others to improve RR-TB care for patients worldwide.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ciaa1894_suppl_Supplementary_Material Click here for additional data file.
Notes
Acknowledgments. We would like to acknowledge our patients for their trust in the treating healthcare practitioners, our colleagues from the Department of Health working in RR-TB units implementing new guidelines, and all data encoders at Médecins sans Frontières offices for their work.
Financial support. No external funding was used for this analysis. All work was performed under the usual duties of the Médecins sans Frontières staff.
Potential conflict of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. | BEDAQUILINE, LINEZOLID | DrugsGivenReaction | CC BY-NC-ND | 33372989 | 20,471,124 | 2021-11-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Optic neuritis'. | Safety and Effectiveness of an All-Oral, Bedaquiline-Based, Shorter Treatment Regimen for Rifampicin-Resistant Tuberculosis in High Human Immunodeficiency Virus (HIV) Burden Rural South Africa: A Retrospective Cohort Analysis.
At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.
We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database.
Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants.
An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.
pmcRifampicin-resistant tuberculosis (RR-TB) affects over half a million of people each year. South Africa remains among the countries with the highest TB and RR-TB burden in the world, with an estimated incidence of 520 TB cases per 100 000 in 2018, up to 7% of which are rifampicin-resistant [1]. The treatment of RR-TB can be long and complex, associated with toxic agents, yet with treatment success rates remaining at just over 60% [2–4]. New and repurposed drugs are now available, with South Africa rolling out new regimens in recent years. South African programmatic data were used to update the World Health Organization (WHO) recommendations for the treatment of RR-TB in 2018 and 2019. This led to the most recent WHO recommendation for an all-oral shorter regimen in which bedaquiline (BDQ) replaces the injectable [5]. This regimen, however, still includes ethionamide (ETH), a drug with doubtful efficacy, poorly tolerated by patients, and ranked lower than linezolid (LZD) in the WHO RR-TB drug hierarchy. Linezolid, a drug shown to be associated with better outcomes and lower mortality, is currently still excluded from the WHO-recommended shorter regimen [5, 6]. At the end of 2018, South Africa modified its all-oral regimen, recommending 6 months of BDQ and 2 months of LZD for all patients initiating the shorter 9–12 months RR-TB regimen [7]. We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this “newest” treatment regimen under programmatic conditions.
METHODS
Study Design
This is a retrospective cohort analysis of routinely collected programmatic data of RR-TB patients eligible for a short standardized BDQ-based regimen between 1 July 2018 and 30 April 2019 [7]. Study was conducted at 3 RR-TB facilities in King Cetshwayo District, KwaZulu Natal, South Africa.
Study Setting
King Cetshwayo District has a human immunodeficiency virus (HIV) prevalence of 26.4% in the general population and RR-TB rates of 9–12% among all TB cases [8, 9]. In 2011, Médecins sans Frontières (MSF) began working with the National Department of Health (NDoH) and District Health teams to support decentralization of RR-TB care and to improve access to new regimens. Since 2016, RR-TB treatment is provided at 3 ambulatory sites with a centralized in-patient unit if admission is clinically indicated.
RR-TB Treatment Protocol
On diagnosis of rifampicin resistance (by nucleic acid amplification test [GeneXpert; Cepheid] or line probe assay test [GenoType MTBDRplusV2.0; Hain Lifescience]), patients receive clinical evaluation, baseline examinations, and treatment initiation according to NDoH Guidance at a RR-TB treatment site [7]. One sputum sample is collected for smear, culture, and first- and second-line genotypic resistance testing (culture, GenoType MTBDRplus and GenoType MTBDRsl assay are processed by the referral laboratory of the National Health Laboratory Service [NHLS]). This forms the baseline culture for the patient and is taken within the timeframe of 3 months before to 1 month after treatment start.
The South African standard of care for RR-TB changed during 2018. In July, a BDQ-based regimen was implemented. ETH was removed during the following months (some still receiving ETH initially), and it was advised to treat with LZD until second-line resistance could be excluded. This led to variable durations of LZD among patients. In November 2018, a generalized recommendation of 2 months of LZD for all patients initiating RR-TB treatment was released [7] (Figure 2). In patients with hemoglobin levels <8g/dL, LZD initiation is deferred until anemia improves, sometimes requiring blood transfusion.
Figure 2. Diagrammatic overview of the short standardized Bedaquiline-based regimen, indicating recommended duration of each drug as of November 2018 in South Africa (National Department of Health Interim Guidance for the Implementation of Injectable Free Regimens for Rifampicin-Resistant Tuberculosis).
First follow-up of patients happens 2 weeks after initiation. Specific laboratory tests, including full blood and neutrophil count, are recommended, as well as electrocardiogram (ECG) monitoring. Further follow-ups are at week 4 and then monthly, with regular ECG while on BDQ and laboratory tests indicated by the prescribed medications. Monthly bacteriological monitoring consists of both smear and culture (SC) samples for all patients on treatment. Cultures are done by liquid medium (BACTEC MGIT®). Phenotypic drug susceptibility testing (DST) for first- and second-line drugs happens on all positive cultures. Adverse events (AEs) are managed according to their clinical significance and national guidelines [7].
Study Population
We included all RR-TB patients over 18 years of age, eligible for the short standardized all-oral BDQ-based regimen as per NDoH guidance [7], at Eshowe, Mbongolwane, and Catherine Booth hospitals in King Cetshwayo District between 1 July 2018 and 30 April 2019.
Study Variables and Definitions
WHO and national guidelines were used to define RR-TB resistance type and outcome variables such as time to SC conversion, end-of-treatment outcomes, and AEs [7, 10]. Time to SC conversion was defined as the time from initiation of RR-TB treatment to time of SC conversion. SC conversion was reached with 2 consecutive negative SC results on samples collected at least 30 days apart with conversion date being the collection date of the first negative SC sample [10].
End-of-treatment outcomes were assigned by the treating clinician, in line with both NDoH and WHO definitions [7]. An AE is defined as any “untoward medical occurrence in a patient receiving any kind of treatment” [11]. We looked at AEs up until the end of the 24-week BDQ course. AEs are graded on a scale of 1 to 4, with 1 being mild and 4 being life-threatening [11]. AEs of grade 3 and higher are considered severe. AEs occurring more than once in the same patient were recorded by the date of highest severity. AEs leading to persistent disability or hospitalization were noted as serious AEs. It was difficult, however, to conclude occurrence of AEs as causes of death due to incompleteness of AE reporting, to polypharmacy and comorbidities of patients, and unspecified recording on death certificates. QT intervals are calculated according to Frederica’s formula (QTcF) as recommended per national guidelines [7]. Specific cutoff values for numeric variables of laboratory tests to define grading are taken from the Clinical and Programmatic Guide for Patient Management with New TB Drugs (Common Terminology Criteria for Adverse Events [CTCAE] v.4.03 classification) [11]. For the entire cohort, 2 same medical doctors interpreted treating clinicians’ notes for grading of AEs. All pro-formas were checked for completeness by the principal investigator before final recording.
Data Collection and Analysis
Source documents for our study were NDoH Electronic Drug-resistant Tuberculosis Register (EDRWeb), NHLS results, and facility-based clinical charts. Data were extracted by using a standardized data collection tool (see the Supplementary material). All data were entered into an Epi-Info (Centers for Disease Control and Prevention [CDC], Atlanta, GA, USA) database. Continuous variables are presented as medians with interquartile range (IQR). Categorical variables are presented as frequencies and proportions. A χ 2 test was used to compare categorical variables. Time to SC conversion was estimated using Kaplan-Meier (KM) curves. For the analysis of time to SC conversion, the outcome of interest was SC conversion achieved within 3 or 6 months of treatment. If the outcome of interest was not achieved, it was considered as censored.
Censoring occurs when the patient is lost to follow-up (LTFU) or died before achieving SC conversion. The time of censoring was the date of death or LTFU. Censoring also occurred when the patient did not SC convert within 6 months of treatment or transferred or moved out (TMO) before SC conversion was achieved. In our cohort, however, no patient TMO before SC conversion was achieved, and SC conversion status at month 6 was known for all those with positive baseline SC samples. Log-rank test was used to investigate the difference between survival curves. The median time to SC conversion was reported using 95% confidence interval (CI). Data were analyzed using STATA version 15 (StataCorp, College Station, TX, USA).
Ethics
Ethics approval was obtained by MSF Ethics Review Board (Geneva, Switzerland) and the Biomedical Research Ethics Board of the University of KwaZulu-Natal, South Africa.
RESULTS
Patient Characteristics
From 1 July 2018 to 30 April 2019, 194 patients were notified with RR-TB in our district. The short regimen was initiated in 151 patients, yet 19.9% (30/151) were switched to a longer regimen, when their baseline resistance profiles became available, as per NDoH guidelines. Figure 1 shows the patients eligible for the short standardized BDQ-based course included in the final analysis.
Figure 1. Flow diagram of selection of study participants from patients notified with RR-TB in King Cetshwayo district, Kwa-Zulu Natal, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: DR-TB, drug-resistant tuberculosis; INH, isoniazid; RR-TB, rifampicin-resistant tuberculosis.
Table 1 shows the baseline characteristics of these 117 patients. Of our patients, 59.8% (95% CI: 50.6–68.4) were male, 68.4% (95% CI: 59.3–76.3) living with HIV, and 55.6% (95% CI: 46.3–64.4) had confirmed multidrug resistance (MDR). Of our cohort, 91.5% (95% CI: 84.7–95.4) received both BDQ and LZD; the median time on LZD was 8 (IQR: 6–13) weeks. And 76.9% (95% CI: 68.3–83.6) received their complete RR-TB treatment as out-patients.
Table 1. Demographic and Clinical Characteristics of RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019, n = 117
Patients Characteristics n %/Median 95% CI/IQR
Gender
Female 47 40.2 31.6–49.4
Male 70 59.8 50.6–68.4
Median age (IQR) 117 35 27–44
Age group
14–24 22 18.8 12.6–27.0
25–34 33 28.2 20.7–37.2
35–44 34 29.1 21.5–38.0
45–54 17 14.5 9.2–22.3
≥55 11 9.4 5.2–16.3
Previous TB history
New 63 53.8 44.7–62.8
Had DSTB 50 42.7 34.0–52.0
Had DRTB 4 3.4 1.7–8.9
HIV status
Negative 37 31.6 23.7–40.7
Positive 80 68.4 59.3–76.3
ART status during RR-TB Tx (n = 80)
Lost to follow-up 6 7.5 3.3–15.9
Newly diagnosed 12 15.0 8.6–24.8
Stable on antiretroviral 62 77.5 66.8–85.5
Median CD4 at RR-TB initiation (IQR) 76 243 93–459
CD4 at RR-TB initiation (n = 80)
<100 20 25.0 16.6–35.9
100–200 16 20.0 12.5–30.4
200–350 14 17.5 10.5–27.7
≥350 26 32.5 23.0–43.7
CD4 not done 4 5.0 1.8–12.8
RR-TB type
Rif Res on GXP only 39 33.3 25.3–42.5
Rif monoresistance 11 9.4 5.2–16.3
GXP: Rif Res and 1st line LPA sensitive 2 1.7 .4–6.7
Confirmed MDRa 65 55.6 46.3–64.4
Baseline smear results
Negative 63 53.8 44.7–62.8
Positive 52 44.4 35.6–53.7
Test not done 2 1.7 .4–6.7
Baseline culture results
Negative 32 27.4 19.9–36.3
Positive 67 57.3 48.0–66.0
Contaminated 12 10.3 5.9–17.3
Test not done 6 5.1 2.3–11.1
Hb at baseline
<7.9 9 7.7 4.0–14.2
7.9–9.9 26 22.2 15.5–30.8
≥10 82 70.1 61.1–77.8
QTcF at baseline
<450 112 95.7 90.0–98.2
≥450 4 3.4 1.3–8.9
Missing 1 0.9 .1–6.0
Abbreviations: ART, antiretroviral therapy; BDQ, bedaquiline; CI, confidence interval; GXP, GeneXpert (first line test for any presumptive TB case); Hb, hemoglobin; HIV, human immunodeficiency virus; INH, isoniazid; IQR, interquartile range; LPA, line probe assay; MDR, multidrug resistant (resistant to both rifampicin and isoniazid); QTcF, calculated QT interval according to Frederica’s formula; Rif Res, rifampicin resistant; Rif S, rifampicin sensitive; RR-TB, rifampicin-resistant tuberculosis; TB, tuberculosis.
aIsoniazid resistance in these patients was limited to the presence of a single gene mutation (either katG or inhA), because patients with both mutations do not qualify to receive the shorter regimen [7].
Bacteriological Outcomes
Among 117 patients, 44.4% (95% CI: 35.6–53.7) had a positive smear and 57.3% (95% CI: 48.0–66.0) a positive culture at baseline. And 95 patients (81.2%) completed 6 months of treatment and had a median number of monthly follow-up smear and culture results of 6 (IQR 5–6) and 5 (IQR 4–6), respectively (Table 2). Smear conversion was achieved in 92.3% (95% CI: 80.7–97.2), and 7.7% (95% CI: 2.8–19.3) died within 6 months. Culture conversion was achieved in 89.6% (95% CI: 79.3–95.0), 6.0% (95% CI: 2.2–15.2) died, and 4.5% (95% CI: 1.4–13.3) LTFU within 6 months. The median time to smear conversion was 34 days (95% CI: 29–45) and to culture conversion 56 days (95% CI: 50–57) (Figure 3).
Table 2. Smear and Culture Conversion Status at Month 6 for RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019.
Smear and Culture Follow-up and Conversion Status at Month 6 of Treatment n %/Median 95% CI/IQR
Median number of follow-up smears for all 95 6 5–6
Median number of follow-up smears for smear positive at baseline 41 6 5–6
Smear conversion status (n = 52)
Converted negative 48 92.3 80.7–97.2
Died before conversion 4 7.7 2.8–19.3
LTFU before conversion 0 0.0 N/A
Median number of follow-up cultures for all 95 5 4–6
Median number of follow-up cultures for culture positive at baseline 56 5 4–6
Culture conversion status (n = 67)
Converted negative 60 89.6 79.3–95.0
Died before conversion 4 6.0 2.2–15.2
LTFU before conversion 3 4.5 1.4–13.3
Of total cohort (n = 117), 95 completed 6 months treatment. Of 67 culture positive at baseline, 56 completed 6 months treatment. Of 52 smear positive at baseline, 48 completed 6 months treatment.
Abbreviations: BDQ, bedaquiline; CI, confidence interval; IQR, interquartile range; LTFU, lost to follow-up; N/A, not applicable; RR-TB, rifampicin-resistant tuberculosis.
Figure 3. Kaplan-Meier survival estimates for smear/culture positive RR-TB patients at baseline in King Cetshwayo district, 1 July 2018 to 30 April 2019. A, Time to culture conversion (n = 67). B, Time to smear conversion (n = 52). C, Time to culture conversion by HIV status (n = 67); log-rank test within 6 months of follow-up: P = .104. D, Time to culture conversion by CD4 count (n = 45); log-rank test within 3 months of follow-up: P = .826. Abbreviations: HIV, human immunodeficiency virus; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in HIV-negative patients compared to HIV-positive was 90.0% (95% CI: 64.5–97.8) versus 89.4% (95% CI: 76.2–95.7) (P = .938) (Table 3). The median time to culture conversion for HIV-negative and HIV-positive patients was 36 (95% CI: 29–57) and 57 days (95% CI: 53–64), respectively (P = .104) (Figure 3).
Table 3. Culture Conversion Status at Month 6 of Treatment for HIV-positive Patients with Positive Baseline Culture by HIV status and CD4 Cell Count of RR-TB Patients Initiated and Continued on the Short Standardized BDQ-based Regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019
HIV negative (n = 20) HIV positive (n = 45) CD4 <200 cells/µL (n = 20) CD4 ≥200 cells/µL (n = 25)
Culture Conversion Status at Month 6 n % 95% CI n % 95% CI n % 95% CI n % 95% CI
Converted negative 18 90.0 64.5–97.8 42 89.4 76.2–95.7 17 85.0 59.6–95.6 24 96.0 73.7–99.5
Died before conversion 2 10.0 2.2–35.5 2 4.3 1.0–16.2 1 5.0 .5–32.3 1 4.0 .4–26.3
LTFU before conversion 0 0.0 0.0–0.0 3 6.4 2.0–18.7 2 10.0 2.0–35.5 0 0.0 0–0
χ 2 and P value: HIV-negative vs HIV-positive (.006 and .938). CD4 <200 vs ≥200 (1.66 and .198).
Abbreviations: BDQ, bedaquiline; CI, confidence interval; HIV, human immunodeficiency virus; LTFU, lost to follow-up; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in CD4 count <200 cells/µL compared to CD4 count ≥200 cells/µL was 85.0% (95% CI: 59.6–95.6) versus 96.0% (95% CI: 73.7–99.5) (P = .198) (Table 3). We looked at time to culture conversion up to 3 months considering that 3-months culture conversion was known for 82.2% (95% CI: 67.9–92.0) of patients living with HIV with documented baseline CD4. There was no significant difference between KM survival curves of CD4 groups within 3 months of follow-up (P = .826) (Figure 3). The median time to culture conversion within 6 months follow-up in CD4 levels <200 cells/µL was 64 days (95% CI: 32–113) and with CD4 levels ≥200 cells/µL was 57 days (95% CI: 57–68).
Seven patients had a positive culture during their treatment course after achieving culture conversion. Four of the 7 positive cultures occurred after month 6. The positive cultures showed similar resistance patterns to baseline and patients continued the same regimen. All 7 patients reconverted; 5 successfully completed treatment, 1 patient had TMO, and 1 patient was LTFU. Of patients with negative baseline culture samples, 7 developed a positive culture during treatment. Of these 7, 2 patients had culture results with amplified resistance profiles, compared to baseline line probe assay results.
End-of-Treatment Outcomes
Treatment success was achieved in 75.2% (95% CI: 66.5–82.3) of patients. Mortality was 12.8% (95% CI: 7.8–20.3), and 80% (95% CI: 51.9–95.7) of deaths occurred in the first 4 months of treatment. LTFU, treatment failure, and TMO was recorded in 10.3% (95% CI: 5.9–17.3), .9% (95% CI: .01–6.0), and .9% (95% CI: .01–6.0), respectively.
Adverse Events
A total of 298 AEs was recorded; 108 (92.3% [95% CI: 85.8–96.0]) patients experienced at least 1 AE (grade 1–4) during the BDQ course, with a median of 2 (IQR 2–4) AEs per patient. Looking at severe AEs only, a total of 62 severe AEs were recorded in 43 (36.8% [95% CI: 28.4–46.0]) patients. Anemia was the most frequent and accounted for 27 (43.5% [95% CI: 31.0–56.7]) of all severe AEs (Figure 4). For these 27 patients, the median time to severe anemia was 7.1 (IQR 4.0–12.9) weeks after treatment initiation. Of 107 patients who received LZD, 27 (25.2% [95% CI: 17.3–34.6]) developed severe anemia. Of 15 patients who died, severe anemia occurred in 10 (66.7% [95% CI: 38.4–88.2]) patients. In our cohort, grade 3 and 4 QT prolongation occurred in 7 (6.0% [95% CI: 2.4–11.9]) patients. Other severe AEs documented were hepatotoxicity in 9 (14.5% [95% CI: 6.9–25.8]) patients, QT prolongation in 7 (11.3% [95% CI: 4.7–21.9]) patients, nausea and vomiting in 5 (8.1% [95% CI: 2.7–17.8]) patients, and nephrotoxicity in 4 (6.5% [95% CI: 1.8–15.7]) patients. One patient developed optic neuritis and lost all vision. A different patient developed peripheral neuropathy of the lower limbs and fractured her ankle following gait disturbances. These last 2 AEs met the definition of serious AEs.
Figure 4. Frequency of severe AEs experienced in RR-TB patients during first 24 weeks after treatment initiation (N = 62), receiving a short standardized BDQ-based regimen in King Cetshwayo district between 1 July 2018 and 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; RR-TB, rifampicin-resistant tuberculosis.
Management of Adverse Events
Supportive medication was given for symptom control for 103 (34.6% [95% CI: 29.2–40.3]) AEs. No specific management actions were taken for 119 (39.9% [34.3–45.7]) AEs, due to their transient course, clinical insignificance, and/or planned completion of the course of the causative drug. For 21 (7.0% [95% CI: 4.4–10.6]) AEs, patients were hospitalized for further monitoring and treatment.
Hospitalization after treatment initiation occurred in 26 (22.2% [95% CI: 15.1–30.8]) of our patients for various reasons. Among hospitalizations, 18 (69.2% [95% CI: 48.2–85.7]) were attributed to an AE and the need for inpatient management. Of these AE-linked admissions, 8 (44.4% [95% CI: 21.5–69.2]) were due to severe anemia, and 2 (11.1% [95% CI: 1.4–34.7]) were due to a prolonged QT interval.
LZD was interrupted by the provider in 27 (25.2% [95% CI: 17.8–34.5]) participants; the median time on LZD for these patients was 8 (IQR 4–11) weeks. LZD was reintroduced at a reduced dosage of 300 mg/day in 8 occurrences; 1 patient reinitiated the dosage of 600 mg/day; in the remaining 18 cases, LZD was permanently discontinued and not replaced. This was due to various reasons, including receipt of DST results showing an absence of second-line resistance or clinical improvement of the patient on the regimen, where the risks of LZD were felt to outweigh the benefit of continued use. BDQ was interrupted in 3 patients and reinitiated in all, after review and supportive therapy.
DISCUSSION
The South African all-oral short regimen shows good results in a high HIV burden setting. Treatment success was achieved in 75% of our patients, exceeding historical treatment successes of <65% of both the short injectable regimen and the “BLIX” cohort (BDQ and LZD for XDR patients) within the same area [12, 13]. The success rate is similar to that reported from a national cohort in South Africa where BDQ and LZD were combined in a longer regimen [14]. AEs remain common and were often associated with the use of LZD, but some toxicity occurred to other drugs in the regimen. High-dose isoniazid, pyrazinamide, and ethambutol were frequently interrupted following an AE (Figure 5), calling into question the routine use of these drugs for RR-TB treatment, as their effectiveness is also uncertain [6]. Mortality in our cohort remains high, comparable to other oral regimens for RR-TB [14, 16] and happens early during treatment. This can be due to delayed diagnosis and treatment initiation [17]. Most of our patients received their treatment as outpatients, likely reducing costs within a resource-limited healthcare system yet with risk for LTFU, in absence of proper financial and social support.
Figure 5. Graphic illustration of episodes of treatment interruption (N = 94) per individual drug (drug name; n) following an AE in patients during the first 24 weeks of the short standardized BDQ-based regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; CLF, clofazimine; E, ethambutol; ETH, ethionamide; INH hd, high dose isoniazid; LFX, levofloxacin; LZD, linezolid; PZA, pyrazinamide.
Almost 20% of patients initiated on the short regimen were switched to a longer regimen when their baseline resistance profiles became available [7]. We decided not to include these patients in our analysis, as we wanted to assess both tolerability and effectiveness in the “newest” shorter regimen for eligible RR-TB patients. These 30 patients either had isoniazid (INH) mutations and/or levofloxacin or injectable resistance. Although excluded from our analysis, they represent an important population for additional future study, especially to see if the empiric inclusion of LZD as part of the shorter regimen decreases the likelihood of developing resistance to other administered drugs. As patients are currently started on RR-TB treatment before rapid molecular INH and FLQ-resistance results are available, we believe there is benefit in a robust regimen, including LZD, at treatment initiation.
Nearly all of our patients received both BDQ and LZD. The use of these 2 drugs likely contributed to high rates of almost 90% of SC conversion at month 6, exceeding conversion rates in similar settings [18]. LZD has been associated with improved outcomes in RR-TB patients [3, 19] and adding on LZD to the BDQ-based regimen, forming a robust backbone, could have contributed to the rapid time to culture conversion in our cohort. Our results are consistent with those reported under trial conditions, but they are noteworthy, demonstrating what can be achieved in program conditions with high HIV comorbidity [3, 18, 20–25] present. An important finding in our cohort is that HIV status and CD4 levels had no effect on achieving culture conversion, or on time needed to convert within the first 3 months of treatment, even though almost half of our HIV-positive cohort had advanced HIV disease. We acknowledge our small sample size and are cautious drawing conclusions from our findings; nevertheless, this is encouraging for other countries with high HIV/DRTB burden.
Worldwide concern for BDQ-related cardiotoxicity has promoted frequent ECG monitoring [5, 7], yet QT prolongation was observed in <10.0% of the cohort and contributed minimally to hospitalizations. The safety of BDQ has been reinforced in both HIV-negative and HIV-positive patients over the past few years and we see the same reassuring results [20, 26]. LZD-related toxicities, however, remained a challenge, equally noted in other settings [15, 19, 20, 23]. Anemia was the most frequent recorded severe AE, contributing to treatment discontinuation, hospitalization, and possibly mortality within our cohort. Most of the LZD-related toxicities reversed when the drug was discontinued. The overall frequency of peripheral neuropathy in our cohort is low, as LZD exposure was limited to 2 months and possibly underdiagnosis of the pathology. Considering all LZD-associated toxicities, it is crucial to strictly monitor for myelosuppression and neuropathy and to ensure prompt management happens when toxicity occurs [5, 7, 27].
There are several limitations to our analysis. We look at the cohort retrospectively without any comparison group and therefore cannot exclude a general improvement of care contributing to our results. Our cohort was defined as the patients receiving the newly adopted “all-oral BDQ-based” regimen in South Africa, yet the guidance and final recommendation for this regimen was delayed. This led to variable durations of LZD within our cohort. Our data likely underreport on AEs because we relied on routine program data, characterized by inaccuracies in recording. Trained clinicians performed a systematic audit on all clinical charts and missing laboratory results were retrieved online to minimize incompleteness. Retrieving information on AEs a posteriori made it difficult to conduct any causality assessment. We assessed end-of-treatment outcomes with no further follow-up of our cohort and have no data on recurrence rates of this regimen; final outcomes could differ. Fourteen patients had a positive culture, mostly late in treatment, and could be at higher risk for relapse. Long-term follow-up of RR-TB patients completing treatment is necessary to evaluate relapse risk and long-term effectiveness of the shorter regimen.
CONCLUSION
An all-oral shorter regimen, containing BDQ and LZD, shows excellent outcomes in a high HIV prevalent population and used under rural programmatic conditions. The most common AEs were related to LZD, and specific screening and management strategies are needed to identify bone marrow toxicity, especially after the first month of treatment, associated with this medication. In spite of the effectiveness of this regimen, mortality remained high and there is additional support needed to reduce LTFU as well.
South Africa has shown a way for rapid implementation of new regimens under programmatic conditions, using WHO group A drugs to combat their RR-TB epidemic. Given the effectiveness and the feasibility of this regimen, the country can hopefully serve as a model for others to improve RR-TB care for patients worldwide.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ciaa1894_suppl_Supplementary_Material Click here for additional data file.
Notes
Acknowledgments. We would like to acknowledge our patients for their trust in the treating healthcare practitioners, our colleagues from the Department of Health working in RR-TB units implementing new guidelines, and all data encoders at Médecins sans Frontières offices for their work.
Financial support. No external funding was used for this analysis. All work was performed under the usual duties of the Médecins sans Frontières staff.
Potential conflict of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. | BEDAQUILINE, LINEZOLID | DrugsGivenReaction | CC BY-NC-ND | 33372989 | 20,471,125 | 2021-11-02 |
What was the administration route of drug 'BEDAQUILINE'? | Safety and Effectiveness of an All-Oral, Bedaquiline-Based, Shorter Treatment Regimen for Rifampicin-Resistant Tuberculosis in High Human Immunodeficiency Virus (HIV) Burden Rural South Africa: A Retrospective Cohort Analysis.
At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.
We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database.
Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants.
An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.
pmcRifampicin-resistant tuberculosis (RR-TB) affects over half a million of people each year. South Africa remains among the countries with the highest TB and RR-TB burden in the world, with an estimated incidence of 520 TB cases per 100 000 in 2018, up to 7% of which are rifampicin-resistant [1]. The treatment of RR-TB can be long and complex, associated with toxic agents, yet with treatment success rates remaining at just over 60% [2–4]. New and repurposed drugs are now available, with South Africa rolling out new regimens in recent years. South African programmatic data were used to update the World Health Organization (WHO) recommendations for the treatment of RR-TB in 2018 and 2019. This led to the most recent WHO recommendation for an all-oral shorter regimen in which bedaquiline (BDQ) replaces the injectable [5]. This regimen, however, still includes ethionamide (ETH), a drug with doubtful efficacy, poorly tolerated by patients, and ranked lower than linezolid (LZD) in the WHO RR-TB drug hierarchy. Linezolid, a drug shown to be associated with better outcomes and lower mortality, is currently still excluded from the WHO-recommended shorter regimen [5, 6]. At the end of 2018, South Africa modified its all-oral regimen, recommending 6 months of BDQ and 2 months of LZD for all patients initiating the shorter 9–12 months RR-TB regimen [7]. We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this “newest” treatment regimen under programmatic conditions.
METHODS
Study Design
This is a retrospective cohort analysis of routinely collected programmatic data of RR-TB patients eligible for a short standardized BDQ-based regimen between 1 July 2018 and 30 April 2019 [7]. Study was conducted at 3 RR-TB facilities in King Cetshwayo District, KwaZulu Natal, South Africa.
Study Setting
King Cetshwayo District has a human immunodeficiency virus (HIV) prevalence of 26.4% in the general population and RR-TB rates of 9–12% among all TB cases [8, 9]. In 2011, Médecins sans Frontières (MSF) began working with the National Department of Health (NDoH) and District Health teams to support decentralization of RR-TB care and to improve access to new regimens. Since 2016, RR-TB treatment is provided at 3 ambulatory sites with a centralized in-patient unit if admission is clinically indicated.
RR-TB Treatment Protocol
On diagnosis of rifampicin resistance (by nucleic acid amplification test [GeneXpert; Cepheid] or line probe assay test [GenoType MTBDRplusV2.0; Hain Lifescience]), patients receive clinical evaluation, baseline examinations, and treatment initiation according to NDoH Guidance at a RR-TB treatment site [7]. One sputum sample is collected for smear, culture, and first- and second-line genotypic resistance testing (culture, GenoType MTBDRplus and GenoType MTBDRsl assay are processed by the referral laboratory of the National Health Laboratory Service [NHLS]). This forms the baseline culture for the patient and is taken within the timeframe of 3 months before to 1 month after treatment start.
The South African standard of care for RR-TB changed during 2018. In July, a BDQ-based regimen was implemented. ETH was removed during the following months (some still receiving ETH initially), and it was advised to treat with LZD until second-line resistance could be excluded. This led to variable durations of LZD among patients. In November 2018, a generalized recommendation of 2 months of LZD for all patients initiating RR-TB treatment was released [7] (Figure 2). In patients with hemoglobin levels <8g/dL, LZD initiation is deferred until anemia improves, sometimes requiring blood transfusion.
Figure 2. Diagrammatic overview of the short standardized Bedaquiline-based regimen, indicating recommended duration of each drug as of November 2018 in South Africa (National Department of Health Interim Guidance for the Implementation of Injectable Free Regimens for Rifampicin-Resistant Tuberculosis).
First follow-up of patients happens 2 weeks after initiation. Specific laboratory tests, including full blood and neutrophil count, are recommended, as well as electrocardiogram (ECG) monitoring. Further follow-ups are at week 4 and then monthly, with regular ECG while on BDQ and laboratory tests indicated by the prescribed medications. Monthly bacteriological monitoring consists of both smear and culture (SC) samples for all patients on treatment. Cultures are done by liquid medium (BACTEC MGIT®). Phenotypic drug susceptibility testing (DST) for first- and second-line drugs happens on all positive cultures. Adverse events (AEs) are managed according to their clinical significance and national guidelines [7].
Study Population
We included all RR-TB patients over 18 years of age, eligible for the short standardized all-oral BDQ-based regimen as per NDoH guidance [7], at Eshowe, Mbongolwane, and Catherine Booth hospitals in King Cetshwayo District between 1 July 2018 and 30 April 2019.
Study Variables and Definitions
WHO and national guidelines were used to define RR-TB resistance type and outcome variables such as time to SC conversion, end-of-treatment outcomes, and AEs [7, 10]. Time to SC conversion was defined as the time from initiation of RR-TB treatment to time of SC conversion. SC conversion was reached with 2 consecutive negative SC results on samples collected at least 30 days apart with conversion date being the collection date of the first negative SC sample [10].
End-of-treatment outcomes were assigned by the treating clinician, in line with both NDoH and WHO definitions [7]. An AE is defined as any “untoward medical occurrence in a patient receiving any kind of treatment” [11]. We looked at AEs up until the end of the 24-week BDQ course. AEs are graded on a scale of 1 to 4, with 1 being mild and 4 being life-threatening [11]. AEs of grade 3 and higher are considered severe. AEs occurring more than once in the same patient were recorded by the date of highest severity. AEs leading to persistent disability or hospitalization were noted as serious AEs. It was difficult, however, to conclude occurrence of AEs as causes of death due to incompleteness of AE reporting, to polypharmacy and comorbidities of patients, and unspecified recording on death certificates. QT intervals are calculated according to Frederica’s formula (QTcF) as recommended per national guidelines [7]. Specific cutoff values for numeric variables of laboratory tests to define grading are taken from the Clinical and Programmatic Guide for Patient Management with New TB Drugs (Common Terminology Criteria for Adverse Events [CTCAE] v.4.03 classification) [11]. For the entire cohort, 2 same medical doctors interpreted treating clinicians’ notes for grading of AEs. All pro-formas were checked for completeness by the principal investigator before final recording.
Data Collection and Analysis
Source documents for our study were NDoH Electronic Drug-resistant Tuberculosis Register (EDRWeb), NHLS results, and facility-based clinical charts. Data were extracted by using a standardized data collection tool (see the Supplementary material). All data were entered into an Epi-Info (Centers for Disease Control and Prevention [CDC], Atlanta, GA, USA) database. Continuous variables are presented as medians with interquartile range (IQR). Categorical variables are presented as frequencies and proportions. A χ 2 test was used to compare categorical variables. Time to SC conversion was estimated using Kaplan-Meier (KM) curves. For the analysis of time to SC conversion, the outcome of interest was SC conversion achieved within 3 or 6 months of treatment. If the outcome of interest was not achieved, it was considered as censored.
Censoring occurs when the patient is lost to follow-up (LTFU) or died before achieving SC conversion. The time of censoring was the date of death or LTFU. Censoring also occurred when the patient did not SC convert within 6 months of treatment or transferred or moved out (TMO) before SC conversion was achieved. In our cohort, however, no patient TMO before SC conversion was achieved, and SC conversion status at month 6 was known for all those with positive baseline SC samples. Log-rank test was used to investigate the difference between survival curves. The median time to SC conversion was reported using 95% confidence interval (CI). Data were analyzed using STATA version 15 (StataCorp, College Station, TX, USA).
Ethics
Ethics approval was obtained by MSF Ethics Review Board (Geneva, Switzerland) and the Biomedical Research Ethics Board of the University of KwaZulu-Natal, South Africa.
RESULTS
Patient Characteristics
From 1 July 2018 to 30 April 2019, 194 patients were notified with RR-TB in our district. The short regimen was initiated in 151 patients, yet 19.9% (30/151) were switched to a longer regimen, when their baseline resistance profiles became available, as per NDoH guidelines. Figure 1 shows the patients eligible for the short standardized BDQ-based course included in the final analysis.
Figure 1. Flow diagram of selection of study participants from patients notified with RR-TB in King Cetshwayo district, Kwa-Zulu Natal, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: DR-TB, drug-resistant tuberculosis; INH, isoniazid; RR-TB, rifampicin-resistant tuberculosis.
Table 1 shows the baseline characteristics of these 117 patients. Of our patients, 59.8% (95% CI: 50.6–68.4) were male, 68.4% (95% CI: 59.3–76.3) living with HIV, and 55.6% (95% CI: 46.3–64.4) had confirmed multidrug resistance (MDR). Of our cohort, 91.5% (95% CI: 84.7–95.4) received both BDQ and LZD; the median time on LZD was 8 (IQR: 6–13) weeks. And 76.9% (95% CI: 68.3–83.6) received their complete RR-TB treatment as out-patients.
Table 1. Demographic and Clinical Characteristics of RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019, n = 117
Patients Characteristics n %/Median 95% CI/IQR
Gender
Female 47 40.2 31.6–49.4
Male 70 59.8 50.6–68.4
Median age (IQR) 117 35 27–44
Age group
14–24 22 18.8 12.6–27.0
25–34 33 28.2 20.7–37.2
35–44 34 29.1 21.5–38.0
45–54 17 14.5 9.2–22.3
≥55 11 9.4 5.2–16.3
Previous TB history
New 63 53.8 44.7–62.8
Had DSTB 50 42.7 34.0–52.0
Had DRTB 4 3.4 1.7–8.9
HIV status
Negative 37 31.6 23.7–40.7
Positive 80 68.4 59.3–76.3
ART status during RR-TB Tx (n = 80)
Lost to follow-up 6 7.5 3.3–15.9
Newly diagnosed 12 15.0 8.6–24.8
Stable on antiretroviral 62 77.5 66.8–85.5
Median CD4 at RR-TB initiation (IQR) 76 243 93–459
CD4 at RR-TB initiation (n = 80)
<100 20 25.0 16.6–35.9
100–200 16 20.0 12.5–30.4
200–350 14 17.5 10.5–27.7
≥350 26 32.5 23.0–43.7
CD4 not done 4 5.0 1.8–12.8
RR-TB type
Rif Res on GXP only 39 33.3 25.3–42.5
Rif monoresistance 11 9.4 5.2–16.3
GXP: Rif Res and 1st line LPA sensitive 2 1.7 .4–6.7
Confirmed MDRa 65 55.6 46.3–64.4
Baseline smear results
Negative 63 53.8 44.7–62.8
Positive 52 44.4 35.6–53.7
Test not done 2 1.7 .4–6.7
Baseline culture results
Negative 32 27.4 19.9–36.3
Positive 67 57.3 48.0–66.0
Contaminated 12 10.3 5.9–17.3
Test not done 6 5.1 2.3–11.1
Hb at baseline
<7.9 9 7.7 4.0–14.2
7.9–9.9 26 22.2 15.5–30.8
≥10 82 70.1 61.1–77.8
QTcF at baseline
<450 112 95.7 90.0–98.2
≥450 4 3.4 1.3–8.9
Missing 1 0.9 .1–6.0
Abbreviations: ART, antiretroviral therapy; BDQ, bedaquiline; CI, confidence interval; GXP, GeneXpert (first line test for any presumptive TB case); Hb, hemoglobin; HIV, human immunodeficiency virus; INH, isoniazid; IQR, interquartile range; LPA, line probe assay; MDR, multidrug resistant (resistant to both rifampicin and isoniazid); QTcF, calculated QT interval according to Frederica’s formula; Rif Res, rifampicin resistant; Rif S, rifampicin sensitive; RR-TB, rifampicin-resistant tuberculosis; TB, tuberculosis.
aIsoniazid resistance in these patients was limited to the presence of a single gene mutation (either katG or inhA), because patients with both mutations do not qualify to receive the shorter regimen [7].
Bacteriological Outcomes
Among 117 patients, 44.4% (95% CI: 35.6–53.7) had a positive smear and 57.3% (95% CI: 48.0–66.0) a positive culture at baseline. And 95 patients (81.2%) completed 6 months of treatment and had a median number of monthly follow-up smear and culture results of 6 (IQR 5–6) and 5 (IQR 4–6), respectively (Table 2). Smear conversion was achieved in 92.3% (95% CI: 80.7–97.2), and 7.7% (95% CI: 2.8–19.3) died within 6 months. Culture conversion was achieved in 89.6% (95% CI: 79.3–95.0), 6.0% (95% CI: 2.2–15.2) died, and 4.5% (95% CI: 1.4–13.3) LTFU within 6 months. The median time to smear conversion was 34 days (95% CI: 29–45) and to culture conversion 56 days (95% CI: 50–57) (Figure 3).
Table 2. Smear and Culture Conversion Status at Month 6 for RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019.
Smear and Culture Follow-up and Conversion Status at Month 6 of Treatment n %/Median 95% CI/IQR
Median number of follow-up smears for all 95 6 5–6
Median number of follow-up smears for smear positive at baseline 41 6 5–6
Smear conversion status (n = 52)
Converted negative 48 92.3 80.7–97.2
Died before conversion 4 7.7 2.8–19.3
LTFU before conversion 0 0.0 N/A
Median number of follow-up cultures for all 95 5 4–6
Median number of follow-up cultures for culture positive at baseline 56 5 4–6
Culture conversion status (n = 67)
Converted negative 60 89.6 79.3–95.0
Died before conversion 4 6.0 2.2–15.2
LTFU before conversion 3 4.5 1.4–13.3
Of total cohort (n = 117), 95 completed 6 months treatment. Of 67 culture positive at baseline, 56 completed 6 months treatment. Of 52 smear positive at baseline, 48 completed 6 months treatment.
Abbreviations: BDQ, bedaquiline; CI, confidence interval; IQR, interquartile range; LTFU, lost to follow-up; N/A, not applicable; RR-TB, rifampicin-resistant tuberculosis.
Figure 3. Kaplan-Meier survival estimates for smear/culture positive RR-TB patients at baseline in King Cetshwayo district, 1 July 2018 to 30 April 2019. A, Time to culture conversion (n = 67). B, Time to smear conversion (n = 52). C, Time to culture conversion by HIV status (n = 67); log-rank test within 6 months of follow-up: P = .104. D, Time to culture conversion by CD4 count (n = 45); log-rank test within 3 months of follow-up: P = .826. Abbreviations: HIV, human immunodeficiency virus; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in HIV-negative patients compared to HIV-positive was 90.0% (95% CI: 64.5–97.8) versus 89.4% (95% CI: 76.2–95.7) (P = .938) (Table 3). The median time to culture conversion for HIV-negative and HIV-positive patients was 36 (95% CI: 29–57) and 57 days (95% CI: 53–64), respectively (P = .104) (Figure 3).
Table 3. Culture Conversion Status at Month 6 of Treatment for HIV-positive Patients with Positive Baseline Culture by HIV status and CD4 Cell Count of RR-TB Patients Initiated and Continued on the Short Standardized BDQ-based Regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019
HIV negative (n = 20) HIV positive (n = 45) CD4 <200 cells/µL (n = 20) CD4 ≥200 cells/µL (n = 25)
Culture Conversion Status at Month 6 n % 95% CI n % 95% CI n % 95% CI n % 95% CI
Converted negative 18 90.0 64.5–97.8 42 89.4 76.2–95.7 17 85.0 59.6–95.6 24 96.0 73.7–99.5
Died before conversion 2 10.0 2.2–35.5 2 4.3 1.0–16.2 1 5.0 .5–32.3 1 4.0 .4–26.3
LTFU before conversion 0 0.0 0.0–0.0 3 6.4 2.0–18.7 2 10.0 2.0–35.5 0 0.0 0–0
χ 2 and P value: HIV-negative vs HIV-positive (.006 and .938). CD4 <200 vs ≥200 (1.66 and .198).
Abbreviations: BDQ, bedaquiline; CI, confidence interval; HIV, human immunodeficiency virus; LTFU, lost to follow-up; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in CD4 count <200 cells/µL compared to CD4 count ≥200 cells/µL was 85.0% (95% CI: 59.6–95.6) versus 96.0% (95% CI: 73.7–99.5) (P = .198) (Table 3). We looked at time to culture conversion up to 3 months considering that 3-months culture conversion was known for 82.2% (95% CI: 67.9–92.0) of patients living with HIV with documented baseline CD4. There was no significant difference between KM survival curves of CD4 groups within 3 months of follow-up (P = .826) (Figure 3). The median time to culture conversion within 6 months follow-up in CD4 levels <200 cells/µL was 64 days (95% CI: 32–113) and with CD4 levels ≥200 cells/µL was 57 days (95% CI: 57–68).
Seven patients had a positive culture during their treatment course after achieving culture conversion. Four of the 7 positive cultures occurred after month 6. The positive cultures showed similar resistance patterns to baseline and patients continued the same regimen. All 7 patients reconverted; 5 successfully completed treatment, 1 patient had TMO, and 1 patient was LTFU. Of patients with negative baseline culture samples, 7 developed a positive culture during treatment. Of these 7, 2 patients had culture results with amplified resistance profiles, compared to baseline line probe assay results.
End-of-Treatment Outcomes
Treatment success was achieved in 75.2% (95% CI: 66.5–82.3) of patients. Mortality was 12.8% (95% CI: 7.8–20.3), and 80% (95% CI: 51.9–95.7) of deaths occurred in the first 4 months of treatment. LTFU, treatment failure, and TMO was recorded in 10.3% (95% CI: 5.9–17.3), .9% (95% CI: .01–6.0), and .9% (95% CI: .01–6.0), respectively.
Adverse Events
A total of 298 AEs was recorded; 108 (92.3% [95% CI: 85.8–96.0]) patients experienced at least 1 AE (grade 1–4) during the BDQ course, with a median of 2 (IQR 2–4) AEs per patient. Looking at severe AEs only, a total of 62 severe AEs were recorded in 43 (36.8% [95% CI: 28.4–46.0]) patients. Anemia was the most frequent and accounted for 27 (43.5% [95% CI: 31.0–56.7]) of all severe AEs (Figure 4). For these 27 patients, the median time to severe anemia was 7.1 (IQR 4.0–12.9) weeks after treatment initiation. Of 107 patients who received LZD, 27 (25.2% [95% CI: 17.3–34.6]) developed severe anemia. Of 15 patients who died, severe anemia occurred in 10 (66.7% [95% CI: 38.4–88.2]) patients. In our cohort, grade 3 and 4 QT prolongation occurred in 7 (6.0% [95% CI: 2.4–11.9]) patients. Other severe AEs documented were hepatotoxicity in 9 (14.5% [95% CI: 6.9–25.8]) patients, QT prolongation in 7 (11.3% [95% CI: 4.7–21.9]) patients, nausea and vomiting in 5 (8.1% [95% CI: 2.7–17.8]) patients, and nephrotoxicity in 4 (6.5% [95% CI: 1.8–15.7]) patients. One patient developed optic neuritis and lost all vision. A different patient developed peripheral neuropathy of the lower limbs and fractured her ankle following gait disturbances. These last 2 AEs met the definition of serious AEs.
Figure 4. Frequency of severe AEs experienced in RR-TB patients during first 24 weeks after treatment initiation (N = 62), receiving a short standardized BDQ-based regimen in King Cetshwayo district between 1 July 2018 and 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; RR-TB, rifampicin-resistant tuberculosis.
Management of Adverse Events
Supportive medication was given for symptom control for 103 (34.6% [95% CI: 29.2–40.3]) AEs. No specific management actions were taken for 119 (39.9% [34.3–45.7]) AEs, due to their transient course, clinical insignificance, and/or planned completion of the course of the causative drug. For 21 (7.0% [95% CI: 4.4–10.6]) AEs, patients were hospitalized for further monitoring and treatment.
Hospitalization after treatment initiation occurred in 26 (22.2% [95% CI: 15.1–30.8]) of our patients for various reasons. Among hospitalizations, 18 (69.2% [95% CI: 48.2–85.7]) were attributed to an AE and the need for inpatient management. Of these AE-linked admissions, 8 (44.4% [95% CI: 21.5–69.2]) were due to severe anemia, and 2 (11.1% [95% CI: 1.4–34.7]) were due to a prolonged QT interval.
LZD was interrupted by the provider in 27 (25.2% [95% CI: 17.8–34.5]) participants; the median time on LZD for these patients was 8 (IQR 4–11) weeks. LZD was reintroduced at a reduced dosage of 300 mg/day in 8 occurrences; 1 patient reinitiated the dosage of 600 mg/day; in the remaining 18 cases, LZD was permanently discontinued and not replaced. This was due to various reasons, including receipt of DST results showing an absence of second-line resistance or clinical improvement of the patient on the regimen, where the risks of LZD were felt to outweigh the benefit of continued use. BDQ was interrupted in 3 patients and reinitiated in all, after review and supportive therapy.
DISCUSSION
The South African all-oral short regimen shows good results in a high HIV burden setting. Treatment success was achieved in 75% of our patients, exceeding historical treatment successes of <65% of both the short injectable regimen and the “BLIX” cohort (BDQ and LZD for XDR patients) within the same area [12, 13]. The success rate is similar to that reported from a national cohort in South Africa where BDQ and LZD were combined in a longer regimen [14]. AEs remain common and were often associated with the use of LZD, but some toxicity occurred to other drugs in the regimen. High-dose isoniazid, pyrazinamide, and ethambutol were frequently interrupted following an AE (Figure 5), calling into question the routine use of these drugs for RR-TB treatment, as their effectiveness is also uncertain [6]. Mortality in our cohort remains high, comparable to other oral regimens for RR-TB [14, 16] and happens early during treatment. This can be due to delayed diagnosis and treatment initiation [17]. Most of our patients received their treatment as outpatients, likely reducing costs within a resource-limited healthcare system yet with risk for LTFU, in absence of proper financial and social support.
Figure 5. Graphic illustration of episodes of treatment interruption (N = 94) per individual drug (drug name; n) following an AE in patients during the first 24 weeks of the short standardized BDQ-based regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; CLF, clofazimine; E, ethambutol; ETH, ethionamide; INH hd, high dose isoniazid; LFX, levofloxacin; LZD, linezolid; PZA, pyrazinamide.
Almost 20% of patients initiated on the short regimen were switched to a longer regimen when their baseline resistance profiles became available [7]. We decided not to include these patients in our analysis, as we wanted to assess both tolerability and effectiveness in the “newest” shorter regimen for eligible RR-TB patients. These 30 patients either had isoniazid (INH) mutations and/or levofloxacin or injectable resistance. Although excluded from our analysis, they represent an important population for additional future study, especially to see if the empiric inclusion of LZD as part of the shorter regimen decreases the likelihood of developing resistance to other administered drugs. As patients are currently started on RR-TB treatment before rapid molecular INH and FLQ-resistance results are available, we believe there is benefit in a robust regimen, including LZD, at treatment initiation.
Nearly all of our patients received both BDQ and LZD. The use of these 2 drugs likely contributed to high rates of almost 90% of SC conversion at month 6, exceeding conversion rates in similar settings [18]. LZD has been associated with improved outcomes in RR-TB patients [3, 19] and adding on LZD to the BDQ-based regimen, forming a robust backbone, could have contributed to the rapid time to culture conversion in our cohort. Our results are consistent with those reported under trial conditions, but they are noteworthy, demonstrating what can be achieved in program conditions with high HIV comorbidity [3, 18, 20–25] present. An important finding in our cohort is that HIV status and CD4 levels had no effect on achieving culture conversion, or on time needed to convert within the first 3 months of treatment, even though almost half of our HIV-positive cohort had advanced HIV disease. We acknowledge our small sample size and are cautious drawing conclusions from our findings; nevertheless, this is encouraging for other countries with high HIV/DRTB burden.
Worldwide concern for BDQ-related cardiotoxicity has promoted frequent ECG monitoring [5, 7], yet QT prolongation was observed in <10.0% of the cohort and contributed minimally to hospitalizations. The safety of BDQ has been reinforced in both HIV-negative and HIV-positive patients over the past few years and we see the same reassuring results [20, 26]. LZD-related toxicities, however, remained a challenge, equally noted in other settings [15, 19, 20, 23]. Anemia was the most frequent recorded severe AE, contributing to treatment discontinuation, hospitalization, and possibly mortality within our cohort. Most of the LZD-related toxicities reversed when the drug was discontinued. The overall frequency of peripheral neuropathy in our cohort is low, as LZD exposure was limited to 2 months and possibly underdiagnosis of the pathology. Considering all LZD-associated toxicities, it is crucial to strictly monitor for myelosuppression and neuropathy and to ensure prompt management happens when toxicity occurs [5, 7, 27].
There are several limitations to our analysis. We look at the cohort retrospectively without any comparison group and therefore cannot exclude a general improvement of care contributing to our results. Our cohort was defined as the patients receiving the newly adopted “all-oral BDQ-based” regimen in South Africa, yet the guidance and final recommendation for this regimen was delayed. This led to variable durations of LZD within our cohort. Our data likely underreport on AEs because we relied on routine program data, characterized by inaccuracies in recording. Trained clinicians performed a systematic audit on all clinical charts and missing laboratory results were retrieved online to minimize incompleteness. Retrieving information on AEs a posteriori made it difficult to conduct any causality assessment. We assessed end-of-treatment outcomes with no further follow-up of our cohort and have no data on recurrence rates of this regimen; final outcomes could differ. Fourteen patients had a positive culture, mostly late in treatment, and could be at higher risk for relapse. Long-term follow-up of RR-TB patients completing treatment is necessary to evaluate relapse risk and long-term effectiveness of the shorter regimen.
CONCLUSION
An all-oral shorter regimen, containing BDQ and LZD, shows excellent outcomes in a high HIV prevalent population and used under rural programmatic conditions. The most common AEs were related to LZD, and specific screening and management strategies are needed to identify bone marrow toxicity, especially after the first month of treatment, associated with this medication. In spite of the effectiveness of this regimen, mortality remained high and there is additional support needed to reduce LTFU as well.
South Africa has shown a way for rapid implementation of new regimens under programmatic conditions, using WHO group A drugs to combat their RR-TB epidemic. Given the effectiveness and the feasibility of this regimen, the country can hopefully serve as a model for others to improve RR-TB care for patients worldwide.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ciaa1894_suppl_Supplementary_Material Click here for additional data file.
Notes
Acknowledgments. We would like to acknowledge our patients for their trust in the treating healthcare practitioners, our colleagues from the Department of Health working in RR-TB units implementing new guidelines, and all data encoders at Médecins sans Frontières offices for their work.
Financial support. No external funding was used for this analysis. All work was performed under the usual duties of the Médecins sans Frontières staff.
Potential conflict of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33372989 | 20,471,124 | 2021-11-02 |
What was the administration route of drug 'LINEZOLID'? | Safety and Effectiveness of an All-Oral, Bedaquiline-Based, Shorter Treatment Regimen for Rifampicin-Resistant Tuberculosis in High Human Immunodeficiency Virus (HIV) Burden Rural South Africa: A Retrospective Cohort Analysis.
At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.
We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database.
Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants.
An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.
pmcRifampicin-resistant tuberculosis (RR-TB) affects over half a million of people each year. South Africa remains among the countries with the highest TB and RR-TB burden in the world, with an estimated incidence of 520 TB cases per 100 000 in 2018, up to 7% of which are rifampicin-resistant [1]. The treatment of RR-TB can be long and complex, associated with toxic agents, yet with treatment success rates remaining at just over 60% [2–4]. New and repurposed drugs are now available, with South Africa rolling out new regimens in recent years. South African programmatic data were used to update the World Health Organization (WHO) recommendations for the treatment of RR-TB in 2018 and 2019. This led to the most recent WHO recommendation for an all-oral shorter regimen in which bedaquiline (BDQ) replaces the injectable [5]. This regimen, however, still includes ethionamide (ETH), a drug with doubtful efficacy, poorly tolerated by patients, and ranked lower than linezolid (LZD) in the WHO RR-TB drug hierarchy. Linezolid, a drug shown to be associated with better outcomes and lower mortality, is currently still excluded from the WHO-recommended shorter regimen [5, 6]. At the end of 2018, South Africa modified its all-oral regimen, recommending 6 months of BDQ and 2 months of LZD for all patients initiating the shorter 9–12 months RR-TB regimen [7]. We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this “newest” treatment regimen under programmatic conditions.
METHODS
Study Design
This is a retrospective cohort analysis of routinely collected programmatic data of RR-TB patients eligible for a short standardized BDQ-based regimen between 1 July 2018 and 30 April 2019 [7]. Study was conducted at 3 RR-TB facilities in King Cetshwayo District, KwaZulu Natal, South Africa.
Study Setting
King Cetshwayo District has a human immunodeficiency virus (HIV) prevalence of 26.4% in the general population and RR-TB rates of 9–12% among all TB cases [8, 9]. In 2011, Médecins sans Frontières (MSF) began working with the National Department of Health (NDoH) and District Health teams to support decentralization of RR-TB care and to improve access to new regimens. Since 2016, RR-TB treatment is provided at 3 ambulatory sites with a centralized in-patient unit if admission is clinically indicated.
RR-TB Treatment Protocol
On diagnosis of rifampicin resistance (by nucleic acid amplification test [GeneXpert; Cepheid] or line probe assay test [GenoType MTBDRplusV2.0; Hain Lifescience]), patients receive clinical evaluation, baseline examinations, and treatment initiation according to NDoH Guidance at a RR-TB treatment site [7]. One sputum sample is collected for smear, culture, and first- and second-line genotypic resistance testing (culture, GenoType MTBDRplus and GenoType MTBDRsl assay are processed by the referral laboratory of the National Health Laboratory Service [NHLS]). This forms the baseline culture for the patient and is taken within the timeframe of 3 months before to 1 month after treatment start.
The South African standard of care for RR-TB changed during 2018. In July, a BDQ-based regimen was implemented. ETH was removed during the following months (some still receiving ETH initially), and it was advised to treat with LZD until second-line resistance could be excluded. This led to variable durations of LZD among patients. In November 2018, a generalized recommendation of 2 months of LZD for all patients initiating RR-TB treatment was released [7] (Figure 2). In patients with hemoglobin levels <8g/dL, LZD initiation is deferred until anemia improves, sometimes requiring blood transfusion.
Figure 2. Diagrammatic overview of the short standardized Bedaquiline-based regimen, indicating recommended duration of each drug as of November 2018 in South Africa (National Department of Health Interim Guidance for the Implementation of Injectable Free Regimens for Rifampicin-Resistant Tuberculosis).
First follow-up of patients happens 2 weeks after initiation. Specific laboratory tests, including full blood and neutrophil count, are recommended, as well as electrocardiogram (ECG) monitoring. Further follow-ups are at week 4 and then monthly, with regular ECG while on BDQ and laboratory tests indicated by the prescribed medications. Monthly bacteriological monitoring consists of both smear and culture (SC) samples for all patients on treatment. Cultures are done by liquid medium (BACTEC MGIT®). Phenotypic drug susceptibility testing (DST) for first- and second-line drugs happens on all positive cultures. Adverse events (AEs) are managed according to their clinical significance and national guidelines [7].
Study Population
We included all RR-TB patients over 18 years of age, eligible for the short standardized all-oral BDQ-based regimen as per NDoH guidance [7], at Eshowe, Mbongolwane, and Catherine Booth hospitals in King Cetshwayo District between 1 July 2018 and 30 April 2019.
Study Variables and Definitions
WHO and national guidelines were used to define RR-TB resistance type and outcome variables such as time to SC conversion, end-of-treatment outcomes, and AEs [7, 10]. Time to SC conversion was defined as the time from initiation of RR-TB treatment to time of SC conversion. SC conversion was reached with 2 consecutive negative SC results on samples collected at least 30 days apart with conversion date being the collection date of the first negative SC sample [10].
End-of-treatment outcomes were assigned by the treating clinician, in line with both NDoH and WHO definitions [7]. An AE is defined as any “untoward medical occurrence in a patient receiving any kind of treatment” [11]. We looked at AEs up until the end of the 24-week BDQ course. AEs are graded on a scale of 1 to 4, with 1 being mild and 4 being life-threatening [11]. AEs of grade 3 and higher are considered severe. AEs occurring more than once in the same patient were recorded by the date of highest severity. AEs leading to persistent disability or hospitalization were noted as serious AEs. It was difficult, however, to conclude occurrence of AEs as causes of death due to incompleteness of AE reporting, to polypharmacy and comorbidities of patients, and unspecified recording on death certificates. QT intervals are calculated according to Frederica’s formula (QTcF) as recommended per national guidelines [7]. Specific cutoff values for numeric variables of laboratory tests to define grading are taken from the Clinical and Programmatic Guide for Patient Management with New TB Drugs (Common Terminology Criteria for Adverse Events [CTCAE] v.4.03 classification) [11]. For the entire cohort, 2 same medical doctors interpreted treating clinicians’ notes for grading of AEs. All pro-formas were checked for completeness by the principal investigator before final recording.
Data Collection and Analysis
Source documents for our study were NDoH Electronic Drug-resistant Tuberculosis Register (EDRWeb), NHLS results, and facility-based clinical charts. Data were extracted by using a standardized data collection tool (see the Supplementary material). All data were entered into an Epi-Info (Centers for Disease Control and Prevention [CDC], Atlanta, GA, USA) database. Continuous variables are presented as medians with interquartile range (IQR). Categorical variables are presented as frequencies and proportions. A χ 2 test was used to compare categorical variables. Time to SC conversion was estimated using Kaplan-Meier (KM) curves. For the analysis of time to SC conversion, the outcome of interest was SC conversion achieved within 3 or 6 months of treatment. If the outcome of interest was not achieved, it was considered as censored.
Censoring occurs when the patient is lost to follow-up (LTFU) or died before achieving SC conversion. The time of censoring was the date of death or LTFU. Censoring also occurred when the patient did not SC convert within 6 months of treatment or transferred or moved out (TMO) before SC conversion was achieved. In our cohort, however, no patient TMO before SC conversion was achieved, and SC conversion status at month 6 was known for all those with positive baseline SC samples. Log-rank test was used to investigate the difference between survival curves. The median time to SC conversion was reported using 95% confidence interval (CI). Data were analyzed using STATA version 15 (StataCorp, College Station, TX, USA).
Ethics
Ethics approval was obtained by MSF Ethics Review Board (Geneva, Switzerland) and the Biomedical Research Ethics Board of the University of KwaZulu-Natal, South Africa.
RESULTS
Patient Characteristics
From 1 July 2018 to 30 April 2019, 194 patients were notified with RR-TB in our district. The short regimen was initiated in 151 patients, yet 19.9% (30/151) were switched to a longer regimen, when their baseline resistance profiles became available, as per NDoH guidelines. Figure 1 shows the patients eligible for the short standardized BDQ-based course included in the final analysis.
Figure 1. Flow diagram of selection of study participants from patients notified with RR-TB in King Cetshwayo district, Kwa-Zulu Natal, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: DR-TB, drug-resistant tuberculosis; INH, isoniazid; RR-TB, rifampicin-resistant tuberculosis.
Table 1 shows the baseline characteristics of these 117 patients. Of our patients, 59.8% (95% CI: 50.6–68.4) were male, 68.4% (95% CI: 59.3–76.3) living with HIV, and 55.6% (95% CI: 46.3–64.4) had confirmed multidrug resistance (MDR). Of our cohort, 91.5% (95% CI: 84.7–95.4) received both BDQ and LZD; the median time on LZD was 8 (IQR: 6–13) weeks. And 76.9% (95% CI: 68.3–83.6) received their complete RR-TB treatment as out-patients.
Table 1. Demographic and Clinical Characteristics of RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019, n = 117
Patients Characteristics n %/Median 95% CI/IQR
Gender
Female 47 40.2 31.6–49.4
Male 70 59.8 50.6–68.4
Median age (IQR) 117 35 27–44
Age group
14–24 22 18.8 12.6–27.0
25–34 33 28.2 20.7–37.2
35–44 34 29.1 21.5–38.0
45–54 17 14.5 9.2–22.3
≥55 11 9.4 5.2–16.3
Previous TB history
New 63 53.8 44.7–62.8
Had DSTB 50 42.7 34.0–52.0
Had DRTB 4 3.4 1.7–8.9
HIV status
Negative 37 31.6 23.7–40.7
Positive 80 68.4 59.3–76.3
ART status during RR-TB Tx (n = 80)
Lost to follow-up 6 7.5 3.3–15.9
Newly diagnosed 12 15.0 8.6–24.8
Stable on antiretroviral 62 77.5 66.8–85.5
Median CD4 at RR-TB initiation (IQR) 76 243 93–459
CD4 at RR-TB initiation (n = 80)
<100 20 25.0 16.6–35.9
100–200 16 20.0 12.5–30.4
200–350 14 17.5 10.5–27.7
≥350 26 32.5 23.0–43.7
CD4 not done 4 5.0 1.8–12.8
RR-TB type
Rif Res on GXP only 39 33.3 25.3–42.5
Rif monoresistance 11 9.4 5.2–16.3
GXP: Rif Res and 1st line LPA sensitive 2 1.7 .4–6.7
Confirmed MDRa 65 55.6 46.3–64.4
Baseline smear results
Negative 63 53.8 44.7–62.8
Positive 52 44.4 35.6–53.7
Test not done 2 1.7 .4–6.7
Baseline culture results
Negative 32 27.4 19.9–36.3
Positive 67 57.3 48.0–66.0
Contaminated 12 10.3 5.9–17.3
Test not done 6 5.1 2.3–11.1
Hb at baseline
<7.9 9 7.7 4.0–14.2
7.9–9.9 26 22.2 15.5–30.8
≥10 82 70.1 61.1–77.8
QTcF at baseline
<450 112 95.7 90.0–98.2
≥450 4 3.4 1.3–8.9
Missing 1 0.9 .1–6.0
Abbreviations: ART, antiretroviral therapy; BDQ, bedaquiline; CI, confidence interval; GXP, GeneXpert (first line test for any presumptive TB case); Hb, hemoglobin; HIV, human immunodeficiency virus; INH, isoniazid; IQR, interquartile range; LPA, line probe assay; MDR, multidrug resistant (resistant to both rifampicin and isoniazid); QTcF, calculated QT interval according to Frederica’s formula; Rif Res, rifampicin resistant; Rif S, rifampicin sensitive; RR-TB, rifampicin-resistant tuberculosis; TB, tuberculosis.
aIsoniazid resistance in these patients was limited to the presence of a single gene mutation (either katG or inhA), because patients with both mutations do not qualify to receive the shorter regimen [7].
Bacteriological Outcomes
Among 117 patients, 44.4% (95% CI: 35.6–53.7) had a positive smear and 57.3% (95% CI: 48.0–66.0) a positive culture at baseline. And 95 patients (81.2%) completed 6 months of treatment and had a median number of monthly follow-up smear and culture results of 6 (IQR 5–6) and 5 (IQR 4–6), respectively (Table 2). Smear conversion was achieved in 92.3% (95% CI: 80.7–97.2), and 7.7% (95% CI: 2.8–19.3) died within 6 months. Culture conversion was achieved in 89.6% (95% CI: 79.3–95.0), 6.0% (95% CI: 2.2–15.2) died, and 4.5% (95% CI: 1.4–13.3) LTFU within 6 months. The median time to smear conversion was 34 days (95% CI: 29–45) and to culture conversion 56 days (95% CI: 50–57) (Figure 3).
Table 2. Smear and Culture Conversion Status at Month 6 for RR-TB Patients Initiated and Continued the Short Standardized BDQ-based Regimen in King Cetshwayo District, South Africa, 1 July 2018 to 30 April 2019.
Smear and Culture Follow-up and Conversion Status at Month 6 of Treatment n %/Median 95% CI/IQR
Median number of follow-up smears for all 95 6 5–6
Median number of follow-up smears for smear positive at baseline 41 6 5–6
Smear conversion status (n = 52)
Converted negative 48 92.3 80.7–97.2
Died before conversion 4 7.7 2.8–19.3
LTFU before conversion 0 0.0 N/A
Median number of follow-up cultures for all 95 5 4–6
Median number of follow-up cultures for culture positive at baseline 56 5 4–6
Culture conversion status (n = 67)
Converted negative 60 89.6 79.3–95.0
Died before conversion 4 6.0 2.2–15.2
LTFU before conversion 3 4.5 1.4–13.3
Of total cohort (n = 117), 95 completed 6 months treatment. Of 67 culture positive at baseline, 56 completed 6 months treatment. Of 52 smear positive at baseline, 48 completed 6 months treatment.
Abbreviations: BDQ, bedaquiline; CI, confidence interval; IQR, interquartile range; LTFU, lost to follow-up; N/A, not applicable; RR-TB, rifampicin-resistant tuberculosis.
Figure 3. Kaplan-Meier survival estimates for smear/culture positive RR-TB patients at baseline in King Cetshwayo district, 1 July 2018 to 30 April 2019. A, Time to culture conversion (n = 67). B, Time to smear conversion (n = 52). C, Time to culture conversion by HIV status (n = 67); log-rank test within 6 months of follow-up: P = .104. D, Time to culture conversion by CD4 count (n = 45); log-rank test within 3 months of follow-up: P = .826. Abbreviations: HIV, human immunodeficiency virus; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in HIV-negative patients compared to HIV-positive was 90.0% (95% CI: 64.5–97.8) versus 89.4% (95% CI: 76.2–95.7) (P = .938) (Table 3). The median time to culture conversion for HIV-negative and HIV-positive patients was 36 (95% CI: 29–57) and 57 days (95% CI: 53–64), respectively (P = .104) (Figure 3).
Table 3. Culture Conversion Status at Month 6 of Treatment for HIV-positive Patients with Positive Baseline Culture by HIV status and CD4 Cell Count of RR-TB Patients Initiated and Continued on the Short Standardized BDQ-based Regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019
HIV negative (n = 20) HIV positive (n = 45) CD4 <200 cells/µL (n = 20) CD4 ≥200 cells/µL (n = 25)
Culture Conversion Status at Month 6 n % 95% CI n % 95% CI n % 95% CI n % 95% CI
Converted negative 18 90.0 64.5–97.8 42 89.4 76.2–95.7 17 85.0 59.6–95.6 24 96.0 73.7–99.5
Died before conversion 2 10.0 2.2–35.5 2 4.3 1.0–16.2 1 5.0 .5–32.3 1 4.0 .4–26.3
LTFU before conversion 0 0.0 0.0–0.0 3 6.4 2.0–18.7 2 10.0 2.0–35.5 0 0.0 0–0
χ 2 and P value: HIV-negative vs HIV-positive (.006 and .938). CD4 <200 vs ≥200 (1.66 and .198).
Abbreviations: BDQ, bedaquiline; CI, confidence interval; HIV, human immunodeficiency virus; LTFU, lost to follow-up; RR-TB, rifampicin-resistant tuberculosis.
The proportion of 6-months culture conversion in CD4 count <200 cells/µL compared to CD4 count ≥200 cells/µL was 85.0% (95% CI: 59.6–95.6) versus 96.0% (95% CI: 73.7–99.5) (P = .198) (Table 3). We looked at time to culture conversion up to 3 months considering that 3-months culture conversion was known for 82.2% (95% CI: 67.9–92.0) of patients living with HIV with documented baseline CD4. There was no significant difference between KM survival curves of CD4 groups within 3 months of follow-up (P = .826) (Figure 3). The median time to culture conversion within 6 months follow-up in CD4 levels <200 cells/µL was 64 days (95% CI: 32–113) and with CD4 levels ≥200 cells/µL was 57 days (95% CI: 57–68).
Seven patients had a positive culture during their treatment course after achieving culture conversion. Four of the 7 positive cultures occurred after month 6. The positive cultures showed similar resistance patterns to baseline and patients continued the same regimen. All 7 patients reconverted; 5 successfully completed treatment, 1 patient had TMO, and 1 patient was LTFU. Of patients with negative baseline culture samples, 7 developed a positive culture during treatment. Of these 7, 2 patients had culture results with amplified resistance profiles, compared to baseline line probe assay results.
End-of-Treatment Outcomes
Treatment success was achieved in 75.2% (95% CI: 66.5–82.3) of patients. Mortality was 12.8% (95% CI: 7.8–20.3), and 80% (95% CI: 51.9–95.7) of deaths occurred in the first 4 months of treatment. LTFU, treatment failure, and TMO was recorded in 10.3% (95% CI: 5.9–17.3), .9% (95% CI: .01–6.0), and .9% (95% CI: .01–6.0), respectively.
Adverse Events
A total of 298 AEs was recorded; 108 (92.3% [95% CI: 85.8–96.0]) patients experienced at least 1 AE (grade 1–4) during the BDQ course, with a median of 2 (IQR 2–4) AEs per patient. Looking at severe AEs only, a total of 62 severe AEs were recorded in 43 (36.8% [95% CI: 28.4–46.0]) patients. Anemia was the most frequent and accounted for 27 (43.5% [95% CI: 31.0–56.7]) of all severe AEs (Figure 4). For these 27 patients, the median time to severe anemia was 7.1 (IQR 4.0–12.9) weeks after treatment initiation. Of 107 patients who received LZD, 27 (25.2% [95% CI: 17.3–34.6]) developed severe anemia. Of 15 patients who died, severe anemia occurred in 10 (66.7% [95% CI: 38.4–88.2]) patients. In our cohort, grade 3 and 4 QT prolongation occurred in 7 (6.0% [95% CI: 2.4–11.9]) patients. Other severe AEs documented were hepatotoxicity in 9 (14.5% [95% CI: 6.9–25.8]) patients, QT prolongation in 7 (11.3% [95% CI: 4.7–21.9]) patients, nausea and vomiting in 5 (8.1% [95% CI: 2.7–17.8]) patients, and nephrotoxicity in 4 (6.5% [95% CI: 1.8–15.7]) patients. One patient developed optic neuritis and lost all vision. A different patient developed peripheral neuropathy of the lower limbs and fractured her ankle following gait disturbances. These last 2 AEs met the definition of serious AEs.
Figure 4. Frequency of severe AEs experienced in RR-TB patients during first 24 weeks after treatment initiation (N = 62), receiving a short standardized BDQ-based regimen in King Cetshwayo district between 1 July 2018 and 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; RR-TB, rifampicin-resistant tuberculosis.
Management of Adverse Events
Supportive medication was given for symptom control for 103 (34.6% [95% CI: 29.2–40.3]) AEs. No specific management actions were taken for 119 (39.9% [34.3–45.7]) AEs, due to their transient course, clinical insignificance, and/or planned completion of the course of the causative drug. For 21 (7.0% [95% CI: 4.4–10.6]) AEs, patients were hospitalized for further monitoring and treatment.
Hospitalization after treatment initiation occurred in 26 (22.2% [95% CI: 15.1–30.8]) of our patients for various reasons. Among hospitalizations, 18 (69.2% [95% CI: 48.2–85.7]) were attributed to an AE and the need for inpatient management. Of these AE-linked admissions, 8 (44.4% [95% CI: 21.5–69.2]) were due to severe anemia, and 2 (11.1% [95% CI: 1.4–34.7]) were due to a prolonged QT interval.
LZD was interrupted by the provider in 27 (25.2% [95% CI: 17.8–34.5]) participants; the median time on LZD for these patients was 8 (IQR 4–11) weeks. LZD was reintroduced at a reduced dosage of 300 mg/day in 8 occurrences; 1 patient reinitiated the dosage of 600 mg/day; in the remaining 18 cases, LZD was permanently discontinued and not replaced. This was due to various reasons, including receipt of DST results showing an absence of second-line resistance or clinical improvement of the patient on the regimen, where the risks of LZD were felt to outweigh the benefit of continued use. BDQ was interrupted in 3 patients and reinitiated in all, after review and supportive therapy.
DISCUSSION
The South African all-oral short regimen shows good results in a high HIV burden setting. Treatment success was achieved in 75% of our patients, exceeding historical treatment successes of <65% of both the short injectable regimen and the “BLIX” cohort (BDQ and LZD for XDR patients) within the same area [12, 13]. The success rate is similar to that reported from a national cohort in South Africa where BDQ and LZD were combined in a longer regimen [14]. AEs remain common and were often associated with the use of LZD, but some toxicity occurred to other drugs in the regimen. High-dose isoniazid, pyrazinamide, and ethambutol were frequently interrupted following an AE (Figure 5), calling into question the routine use of these drugs for RR-TB treatment, as their effectiveness is also uncertain [6]. Mortality in our cohort remains high, comparable to other oral regimens for RR-TB [14, 16] and happens early during treatment. This can be due to delayed diagnosis and treatment initiation [17]. Most of our patients received their treatment as outpatients, likely reducing costs within a resource-limited healthcare system yet with risk for LTFU, in absence of proper financial and social support.
Figure 5. Graphic illustration of episodes of treatment interruption (N = 94) per individual drug (drug name; n) following an AE in patients during the first 24 weeks of the short standardized BDQ-based regimen in King Cetshwayo district, South Africa, 1 July 2018 to 30 April 2019. Abbreviations: AE, adverse event; BDQ, bedaquiline; CLF, clofazimine; E, ethambutol; ETH, ethionamide; INH hd, high dose isoniazid; LFX, levofloxacin; LZD, linezolid; PZA, pyrazinamide.
Almost 20% of patients initiated on the short regimen were switched to a longer regimen when their baseline resistance profiles became available [7]. We decided not to include these patients in our analysis, as we wanted to assess both tolerability and effectiveness in the “newest” shorter regimen for eligible RR-TB patients. These 30 patients either had isoniazid (INH) mutations and/or levofloxacin or injectable resistance. Although excluded from our analysis, they represent an important population for additional future study, especially to see if the empiric inclusion of LZD as part of the shorter regimen decreases the likelihood of developing resistance to other administered drugs. As patients are currently started on RR-TB treatment before rapid molecular INH and FLQ-resistance results are available, we believe there is benefit in a robust regimen, including LZD, at treatment initiation.
Nearly all of our patients received both BDQ and LZD. The use of these 2 drugs likely contributed to high rates of almost 90% of SC conversion at month 6, exceeding conversion rates in similar settings [18]. LZD has been associated with improved outcomes in RR-TB patients [3, 19] and adding on LZD to the BDQ-based regimen, forming a robust backbone, could have contributed to the rapid time to culture conversion in our cohort. Our results are consistent with those reported under trial conditions, but they are noteworthy, demonstrating what can be achieved in program conditions with high HIV comorbidity [3, 18, 20–25] present. An important finding in our cohort is that HIV status and CD4 levels had no effect on achieving culture conversion, or on time needed to convert within the first 3 months of treatment, even though almost half of our HIV-positive cohort had advanced HIV disease. We acknowledge our small sample size and are cautious drawing conclusions from our findings; nevertheless, this is encouraging for other countries with high HIV/DRTB burden.
Worldwide concern for BDQ-related cardiotoxicity has promoted frequent ECG monitoring [5, 7], yet QT prolongation was observed in <10.0% of the cohort and contributed minimally to hospitalizations. The safety of BDQ has been reinforced in both HIV-negative and HIV-positive patients over the past few years and we see the same reassuring results [20, 26]. LZD-related toxicities, however, remained a challenge, equally noted in other settings [15, 19, 20, 23]. Anemia was the most frequent recorded severe AE, contributing to treatment discontinuation, hospitalization, and possibly mortality within our cohort. Most of the LZD-related toxicities reversed when the drug was discontinued. The overall frequency of peripheral neuropathy in our cohort is low, as LZD exposure was limited to 2 months and possibly underdiagnosis of the pathology. Considering all LZD-associated toxicities, it is crucial to strictly monitor for myelosuppression and neuropathy and to ensure prompt management happens when toxicity occurs [5, 7, 27].
There are several limitations to our analysis. We look at the cohort retrospectively without any comparison group and therefore cannot exclude a general improvement of care contributing to our results. Our cohort was defined as the patients receiving the newly adopted “all-oral BDQ-based” regimen in South Africa, yet the guidance and final recommendation for this regimen was delayed. This led to variable durations of LZD within our cohort. Our data likely underreport on AEs because we relied on routine program data, characterized by inaccuracies in recording. Trained clinicians performed a systematic audit on all clinical charts and missing laboratory results were retrieved online to minimize incompleteness. Retrieving information on AEs a posteriori made it difficult to conduct any causality assessment. We assessed end-of-treatment outcomes with no further follow-up of our cohort and have no data on recurrence rates of this regimen; final outcomes could differ. Fourteen patients had a positive culture, mostly late in treatment, and could be at higher risk for relapse. Long-term follow-up of RR-TB patients completing treatment is necessary to evaluate relapse risk and long-term effectiveness of the shorter regimen.
CONCLUSION
An all-oral shorter regimen, containing BDQ and LZD, shows excellent outcomes in a high HIV prevalent population and used under rural programmatic conditions. The most common AEs were related to LZD, and specific screening and management strategies are needed to identify bone marrow toxicity, especially after the first month of treatment, associated with this medication. In spite of the effectiveness of this regimen, mortality remained high and there is additional support needed to reduce LTFU as well.
South Africa has shown a way for rapid implementation of new regimens under programmatic conditions, using WHO group A drugs to combat their RR-TB epidemic. Given the effectiveness and the feasibility of this regimen, the country can hopefully serve as a model for others to improve RR-TB care for patients worldwide.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
ciaa1894_suppl_Supplementary_Material Click here for additional data file.
Notes
Acknowledgments. We would like to acknowledge our patients for their trust in the treating healthcare practitioners, our colleagues from the Department of Health working in RR-TB units implementing new guidelines, and all data encoders at Médecins sans Frontières offices for their work.
Financial support. No external funding was used for this analysis. All work was performed under the usual duties of the Médecins sans Frontières staff.
Potential conflict of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33372989 | 20,471,124 | 2021-11-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fungal infection'. | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | AMPHOTERICIN B, BASILIXIMAB, CEFEPIME HYDROCHLORIDE, LEVOFLOXACIN, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infective aortitis'. | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | AMPHOTERICIN B, BASILIXIMAB, CEFEPIME HYDROCHLORIDE, LEVOFLOXACIN, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocardial necrosis'. | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | AMPHOTERICIN B, BASILIXIMAB, CEFEPIME HYDROCHLORIDE, LEVOFLOXACIN, MEROPENEM, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY-NC-ND | 33376674 | 19,860,331 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | AMPHOTERICIN B, BASILIXIMAB, CEFEPIME HYDROCHLORIDE, LEVOFLOXACIN, MEROPENEM, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY-NC-ND | 33376674 | 19,860,331 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | AMPHOTERICIN B, BASILIXIMAB, CEFEPIME HYDROCHLORIDE, HEPARIN SODIUM, LEVOFLOXACIN, MEROPENEM, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33376674 | 19,910,647 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Septic embolus'. | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | AMPHOTERICIN B, BASILIXIMAB, CEFEPIME HYDROCHLORIDE, LEVOFLOXACIN, MEROPENEM, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, VANCOMYCIN, VORICONAZOLE | DrugsGivenReaction | CC BY-NC-ND | 33376674 | 19,860,331 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tachycardia'. | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | AMPHOTERICIN B, BASILIXIMAB, CEFEPIME HYDROCHLORIDE, HEPARIN SODIUM, LEVOFLOXACIN, MEROPENEM, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33376674 | 19,910,647 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tachypnoea'. | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | AMPHOTERICIN B, BASILIXIMAB, CEFEPIME HYDROCHLORIDE, HEPARIN SODIUM, LEVOFLOXACIN, MEROPENEM, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33376674 | 19,910,647 | 2021 |
What was the administration route of drug 'AMPHOTERICIN B'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Respiratory (inhalation) | DrugAdministrationRoute | CC BY-NC-ND | 33376674 | 19,900,904 | 2021 |
What was the administration route of drug 'CEFEPIME HYDROCHLORIDE'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376674 | 19,900,904 | 2021 |
What was the administration route of drug 'HEPARIN SODIUM'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376674 | 19,910,647 | 2021 |
What was the administration route of drug 'LEVOFLOXACIN'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376674 | 19,900,904 | 2021 |
What was the administration route of drug 'MEROPENEM'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376674 | 19,900,904 | 2021 |
What was the administration route of drug 'MYCOPHENOLATE MOFETIL'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376674 | 19,900,904 | 2021 |
What was the administration route of drug 'VANCOMYCIN HYDROCHLORIDE'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376674 | 19,900,904 | 2021 |
What was the administration route of drug 'VANCOMYCIN'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
What was the administration route of drug 'VORICONAZOLE'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376674 | 19,900,904 | 2021 |
What was the dosage of drug 'BASILIXIMAB'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
What was the dosage of drug 'CEFEPIME HYDROCHLORIDE'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
What was the dosage of drug 'LEVOFLOXACIN'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
What was the dosage of drug 'MYCOPHENOLATE MOFETIL'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
What was the dosage of drug 'VANCOMYCIN'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
What was the dosage of drug 'VORICONAZOLE'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33376674 | 19,771,864 | 2021 |
What was the outcome of reaction 'Acute myocardial infarction'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,900,904 | 2021 |
What was the outcome of reaction 'Aortitis'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,846,529 | 2021 |
What was the outcome of reaction 'Arterial thrombosis'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,846,529 | 2021 |
What was the outcome of reaction 'Arteritis coronary'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,846,529 | 2021 |
What was the outcome of reaction 'Bronchitis'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,846,529 | 2021 |
What was the outcome of reaction 'Disseminated mucormycosis'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,838,396 | 2021 |
What was the outcome of reaction 'Mediastinitis'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,846,529 | 2021 |
What was the outcome of reaction 'Mucormycosis'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,900,904 | 2021 |
What was the outcome of reaction 'Myocardial necrosis'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,860,331 | 2021 |
What was the outcome of reaction 'Septic embolus'? | Acute myocardial infarction secondary to mucormycosis after lung transplantation.
We present a case of a 57-year-old man who underwent bilateral lung transplantation for idiopathic pulmonary fibrosis. His immediately post-operative course was complicated by fever and cardiac arrest. Despite supportive care and broad-spectrum antibiotics, he experienced continued clinical decline. Autopsy results indicated angioinvasive mucormycosis and coronary arteritis resulting in acute myocardial infarction as the cause of death.
Case presentation
A 57-year-old man with idiopathic pulmonary fibrosis was evaluated for lung transplantation. His past medical history was significant for hypertension, dyslipidemia and chronic total occlusion of the right coronary artery with good collateral blood flow from the circumflex artery. After a negative stress test, he was listed for bilateral lung transplantation. The donor was a healthy, 30-year-old man who succumbed to injuries from motorcycle accident. Donor lung imaging revealed metallic debris in the left-sided airways indicating dirt contamination (Fig. 1a). Bronchoscopic examination revealed debris in the airway consistent with gravel, and it was therapeutically cleared. The donor was treated with intravenous vancomycin and cefepime, and after resolution of airway sections, improvement on chest imaging and demonstration of excellent graft function, the lungs were accepted for transplantation. The patient underwent an uneventful bilateral lung transplantation. Induction therapy consisted of basiliximab, methylprednisolone, and mycophenolate mofetil and the patient received intravenous (IV) vancomycin, levofloxacin, cefepime and inhaled amphotericin prophylactically. Donor cultures grew multiple organisms, including Enterobacter cloacae, Escherichia vulneris, Bacillus, Coagulase-negative staphylococcus, Mycobacterium species, Candida keyfre, Aspergillus ochraceus and Fusarium spp, for which IV voriconazole was added to the patient’s antibiotic regimen.Fig. 1 Autopsy findings. Fig. 1A shows chest CT scan of the donor with evidence of debris in left main bronchus (left) and metallic debris extending into left lower lobe bronchi (right) concerning for foreign body aspiration. Fig. 1B shows necrotic skin lesions on the left chest wall extending on to the flank, indicative of invasive fungal infection. Fig. 1C shows hematoxylin & eosin (H&E) staining of lung allograft demonstrating delicate alveolar septae and intense capillary vascular congestion but no obvious fungal infection. Fig. 1D shows Grocott-Gomori's methenamine silver (GMS) stain of right mainstem bronchus with evidence of invasive fungal infection. Fig. 1E shows high power magnification of the bronchus reveals broad, sparsely septate thin walled hyphae consistent with Apophysomyces elegans. Fig. 1F shows H&E stain of aorta reveals aortitis with intramural thrombus (asterisk). Fig. 1G shows GMS stain of the aorta with evidence of angioinvasive fungal aortitis with near total thrombotic occlusion (asterisk). Fig. 1H shows gross cardiac autopsy reveals epicardial necrosis (black asterisk), left ventricular posterior-lateral wall necrosis (white asterisk) and Left anterior descending coronary artery occlusion (arrow). Thrombosis of LAD without plaque is consistent with septic embolization (insert). Fig. 1I shows GMS stain of epicardial coronary artery revealing angioinvasive coronary arteritis with thrombotic occlusion (asterisk).
Fig. 1
On the fifth postoperative day, the patient developed a fever of 101.9 °F along with tachycardia and tachypnea. Blood cultures and bronchoscopic cultures were obtained, and IV cefepime was switched to IV meropenem. The following day, he suffered a cardiac arrest with pulseless electrical activity (PEA) requiring cardiopulmonary resuscitation for 14 min; return of spontaneous circulation was achieved. Arterial blood gas and routine chemistries did not reveal an obvious cause for PEA arrest. He was intubated and veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support was initiated, and a transesophageal echocardiogram revealed akinesis of inferior and lateral walls and newly reduced left ventricular ejection fraction of 35 %. EKG revealed ST-segment elevation in the infero-lateral wall leads (aVF, V5 and V6), and troponin I levels rose to > 200 ng/mL raising concerns for an acute myocardial infarction. Coronary angiogram revealed 100 % occlusion of left circumflex artery without coronary atherosclerosis. Balloon angioplasty was performed with recanalization of circumflex artery up to first obtuse marginal artery, and an intra-aortic balloon pump was inserted. The patient was initiated on IV heparin. Despite these measures, the patient continued to require escalating doses of vasopressors and developed acute kidney injury requiring continuous renal replacement therapy. Serial echocardiograms revealed globally akinetic ventricles progressing to complete cardiac standstill. Care was withdrawn at that time, and an autopsy was performed.
Autopsy report
Grossly, patient’s skin had patches of necrotic areas along the left chest all extending on to the flank (Fig. 1b). Lungs revealed intact, delicate alveolar septae with diffuse vascular congestion (Fig. 1c). Bronchi revealed invasive fungal infection (Fig. 1d) with broad, sparsely septated thin-walled hyphae consistent with Apophysomyces elegans, a fungus of the order Mucorales (Fig. 1e). There was evidence of aortitis (Fig. 1f) with near total luminal occlusion (Fig. 1g). Cardiac autopsy revealed multifocal coronary artery thrombosis without plaque, consistent with septic embolization, along with myocardial and epicardial necrosis (Fig. 1h). Examination of the coronary arteries revealed angioinvasive arteritis with thrombotic occlusion (Fig. 1i).
Discussion
Infections in the immediate post-transplant period are either donor-derived or nosocomial [1]. Incidence of donor-derived infections in solid organ transplant recipients varies from 2.1%–23.4% [2] and can be classified as expected (known infection present in the donor) or unexpected [3]. The rate of transmission is also affected by the inoculum of pathogens, the organ transplanted, the use of different immunosuppressive agents and use of peri-operative antimicrobial prophylaxis [4]. In lung transplant recipients, the most common donor derived infections are bacterial pneumonias [5]. Fungal infections are less common [6] and are usually caused by Candida or Aspergillus followed by Mucorales, Fusarium and Scedosporium [7]. Mucormycosis is a rare invasive fungal infection caused by fungi of the order Mucorales that includes Rhizopus, Mucor, Rhizomucor, Cunninghamella, Lichtheimia, Saksenaea, and Apophysomyces. They are ubiquitous in nature, found in decaying vegetation and soil. In immunosuppressed patients, they cause vascular invasion with subsequent infarction and necrosis of the affected organs [8]. In transplanted lungs, mucormycosis can affect bronchial anastomoses or pulmonary parenchyma and is associated with high mortality rates. As in our case, blood and respiratory cultures are usually negative, and mucormycosis is usually diagnosed by direct examination or post-mortem culture of the affected tissue [9]. Transmission of mucormycetes from the organ itself is rare, but it is associated with high mortality [3]. Treatment includes early surgical debridement in combination with IV amphotericin-B [3,10]. Azole antifungals such as posaconazole or isavuconazonium can be considered as salvage treatment or when clinical stability is achieved, but not as first-line therapy [10]. While use of prophylactic antifungal agents could prevent many of potentially transmissible fungal infections, it is unlikely that those would have been of help in our patient’s case due to the heavy inoculum.
Clinical course
The patient developed angioinvasive mucormycosis with Apophysomyces elegans, resulting in mediastinitis, bronchitis, aortitis and coronary arteritis with in situ coronary arterial thrombosis and subsequent acute myocardial infarction. The clinical presentation mimicked acute myocardial infarction in that the patient had ST-elevation, elevated cardiac biomarkers, and regional wall motion abnormalities. On coronary angiogram, the presence of multi-focal coronary artery thrombosis without underlying coronary plaques suggested septic embolization. Although autopsy confirmed invasive mucormycosis, multiple cultures during the patient’s hospital course did not yield Apophysomyces elegans, thereby delaying initiation of IV amphotericin B. We suspect that the source of angioinvasive mucormycosis in our patient was aspiration of soil and foreign debris during the motorcycle accident. It is likely that after deposition of apophysomyces in the alveoli, the use of high dose steroids and basiliximab facilitated angioinvasive disease and rapid dissemination to other vascular structures.
Conclusion
This case of an invasive mold infection leading to life-threatening illness in an immunocompromised patient presented clinically as acute myocardial infarction. Donor-derived fungal infections in lung transplant recipients can result in graft loss and high mortality, and due to the angioinvasive nature of mucormycosis, its clinical presentation can mimic organ infarction. Given the difficulty of isolating these organisms in standard culture and high mortality rates associated with these infections, consideration of broadening antifungal coverage to liposomal amphotericin B early in a patient’s clinical course should be considered when fungal infection is suspected. Additionally, donor lung contamination with soil should be considered during the donor evaluation process, as it can be the source of invasive mold infection.
Funding
None.
Acknowledgement
Written consent for this case report was obtained from the patient’s family. | Fatal | ReactionOutcome | CC BY-NC-ND | 33376674 | 19,860,331 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Diagnosing and managing adrenal crisis in pregnancy: A case report.
The diagnosis of adrenal insufficiency in pregnancy is relatively rare. Further, making this diagnosis can be challenging as many of the symptoms overlap with normal symptoms of pregnancy. Given the potential for severe maternal and fetal morbidity and mortality, early recognition and prompt comprehensive treatment are critical.
A 24-year-old woman, G3 P2002, at 17 + 1 weeks of gestation with unremarkable prenatal course was admitted to hospital for hyperemesis gravidarum in the setting of parainfluenza with a notable blood glucose of 20 mg/dL. On hospital day two, she was transferred to intensive care after developing significant hypotension, hyponatremia, and a new finding of hypothyroidism. During her evaluation in the ICU, she was diagnosed with adrenal crisis and she showed significant improvement with glucocorticoid therapy.
There is a paucity of literature regarding diagnosing adrenal insufficiency in pregnancy. Adrenal crisis in pregnancy can present with symptoms similar to severe nausea and vomiting of pregnancy or hyperemesis gravidarum. Additionally, several critical laboratory tests to support the proper diagnosis require time that acute patients cannot always afford. In this patient's case, the diagnosis was made empirically with improvement after glucocorticoid administration, and was later confirmed by laboratory testing. This case highlights the importance of including adrenal insufficiency in the differential diagnosis of hyperemesis patients in order to quickly manage and treat these often acutely and severely ill patients.
1 Introduction
The adrenal cortex takes part in steroidogenesis, producing glucocorticoids, and androgen precursors. An understanding of the hypothalamic-pituitary-adrenal (HPA) axis aids in understanding the pathophysiology of adrenal disorders. In response to stressors, the hypothalamus makes and secretes corticotopin-releasing hormone (CRH), which then binds to receptors on the anterior pituitary, releasing adrenocorticotropic hormone (ACTH) into circulation. This ACTH then binds to receptors on the adrenal cortex to induce synthesis of glucocorticoids. Cortisol is the major glucocorticoid, and increases in response to stress, which activates the HPA axis. Therefore, all of its functions can be thought to allow the body to function at an increased level of physiologic stress. There are several opportunities for pathologic dysfunction through this complex system, including primary, secondary, or tertiary causes of adrenal disorders [1,2].
The fetoplacental unit plays a major role in cortisol levels in pregnancy [3]. In women with intact adrenal function, the plasma levels of free cortisol, CRH, and cortisol-binding globulin all increase in pregnancy [4]. These hormone levels increase with increasing gestational age. When comparing elevations in maternal total serum cortisol levels to those in non-pregnant controls, a mean increase of 1.3, 2.0 and 2.4 times the normal were found in the 1st, 2nd, and 3rd trimester, respectively [5]. These total and free cortisol level increases are thought to be due to increases in CRH and ACTH from the placenta. Even with these average increases in cortisol levels, the amplitude is poorly understood, and exact reference values have yet to be established [3]. With this brief review, this case highlights a rare case of adrenal crisis developing in pregnancy in a patient with no known history of adrenal dysfunction.
2 Case
A 24-year-old woman, gravida 3 para 2, at 17 = +1 weeks of gestation presented to an acute care center for persistent nausea and vomiting that had begun earlier that morning. Her prenatal course was previously complicated by mild nausea and vomiting of pregnancy. On arrival, she reported lightheadedness and there was concern for confusion and altered mental status by the provider who initially evaluated her. Her vitals were notable for blood pressures in the 100 s/60s and mild tachycardia to the low 100 beats per minute. Notably, a fingerstick blood glucose level was collected given her altered mental status and was found to be 20 mg/dL. She was immediately resuscitated with intravenous fluids with dextrose and antiemetics, with rapid improvement of her blood glucose levels, mental status, and overall symptomatology. She was then transferred for inpatient management and monitoring.
On arrival at the inpatient floor, the patient reported overall improvement. Her blood pressures and symptoms then remained stable overnight. Her review of systems was positive for new-onset nasal congestion, rhinitis, and cough that had begun the same morning as her presenting symptoms of nausea and vomiting. The patient revealed in interview that on several occasions in her prior pregnancies, she had low blood glucose levels associated with nausea and vomiting, requiring intravenous glucose. Her past medical history was significant for mild, intermittent asthma, anemia, and allergic rhinitis and her obstetric history included two prior term, uncomplicated, spontaneous vaginal deliveries. Her family history was notable for a diagnosis of systemic lupus erythematosus in her father.
After initial stabilization, patient developed hypotension with tachycardia despite resuscitation with 2 l of crystalloid fluids, and recurrence of her hypoglycemia without nausea or vomiting. Her rapid viral panel had also resulted by this time positive for parainfluenza virus and her thyroid stimulating hormone had also resulted significant for new hypothyroidism. A rapid response was initiated, and the patient was transferred to the intensive care unit for resuscitation.
On arrival, the critical care team was concerned for adrenal crisis after a trigger from an upper respiratory virus. She was started on intravenous hydrocortisone with immediate improvement in maternal status. She remained stable through the remainder of her hospital stay with regular fetal heart rate checks. Endocrinology assessed this patient and believed she was experiencing adrenal crisis of unknown etiology, potentially secondary to an autoimmune process as supported by several laboratory values collected during her evaluation. In particular, her cortisol level was collected immediately prior to empiric treatment and was found to be 0.5 μg/dL. Additionally, her thyroglobulin antibody level was elevated, consistent with an autoimmune disease process of the thyroid. Finally, her adrenocorticotropin hormone was undetectable on several lab assays, and her prolactin level was 17 μg/L, which is inappropriately low in pregnancy. Her diagnosis of adrenal crisis was supported with immediate improvement with glucocorticoids and a brain MRI that showed a partially empty sella with flattened pituitary gland (Fig. 1), which, although not diagnostic of secondary adrenal dysfunction, can be associated with impairment.Fig. 1 Brain MRI highlighting a partially empty sella (arrow) and flattened pituitary gland.
Fig. 1
3 Discussion
Adrenal insufficiency is defined as the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids. This can be potentially life-threatening, as adrenal physiology is critical in hemodynamic and electrolyte homeostasis. The diagnosis of adrenal insufficiency is based on low morning cortisol concentrations, and this diagnosis is most likely when cortisol is <5 μg/dL [6]. Standard cortisol values are poorly established in pregnancy, and while cortisol is expected to rise with increasing gestational age, reference values in pregnancy have yet to be established [5]. Additionally, an abnormal rise in cortisol levels after a stimulation test of 250 micrograms of cosyntropin can be used to diagnose adrenal insufficiency in pregnancy, for which the minimum expected peak values per trimester are 25, 29, and 32 μg/dL, respectively [5,7].
The majority of adrenal insufficiency cases during pregnancy are diagnosed prior to conception. There is typically a low clinical suspicion of new adrenal insufficiency in pregnancy, given the overlapping signs of symptoms with normal pregnancy, nausea and vomiting in pregnancy, and hyperemesis gravidarum such as fatigue, nausea, vomiting, and mild hypotension [7]. In fact, only 100 cases of adrenal insufficiency have been reported to be diagnosed during pregnancy [8].
Adrenal crisis is an acute form of adrenal insufficiency leading to hemodynamic instability, typically necessitating care in an intensive care unit and immediate intravenous glucocorticoids. When a patient progresses to adrenal crisis, timing often does not allow for cosyntropin or other testing to diagnose adrenal insufficiency, as treating empirically is far more important, as was the case with this patient. Although rare, adrenal crisis is critical to diagnose quickly, as the mortality rate without treatment ranges as high as 35%–45%. Additionally, severe maternal and fetal morbidity of untreated adrenal crisis includes poor wound healing, infection, venous thromboembolism, prolonged hospital stays, fetal intrauterine growth restriction, preterm delivery, and increased risk of Cesarean delivery [3,7]. Even in patients with a known history of adrenal insufficiency in pregnancy, the development of adrenal crisis is rare. In a prospective series of 423 patients with adrenal insufficiency, pregnancy was found to trigger adrenal crisis in 0.2%. In a study of 93 patients with known insufficiency, only 1.1% developed adrenal crisis in pregnancy. The incidence of new-onset adrenal crisis without a known pre-existing adrenal disorder is unknown [7].
As mentioned in the case, this patient's cortisol levels were low and ACTH levels were undetectable on separate laboratory draws. Typically, ACTH increases in proportion to increasing cortisol in pregnancy. While standard average values are poorly established, ACTH has been documented to range anywhere from 10 to 300 pg/mL between 10 and 40 weeks of gestation, respectively [9]. Additionally, her thyroid stimulating hormone was decreased with an increased thyroglobulin antibody, consistent with autoimmune involvement. Finally, her prolactin was within normal range for a nonpregnant woman, which is unusual, as prolactin is typically elevated in pregnancy, ranging from 35 to 600 ng/mL, with increases seen with increasing gestational age [10].
While the trigger of this patient's adrenal insufficiency is unclear, downregulation of the immune system during pregnancy coupled with her acute parainfluenza virus may have contributed to the possible autoimmune process in this case. The maternal immune system is complex in pregnancy. There is evidence that pregnancy causes generalized leukocyte activation with an increase in circulating granulocytes and a decrease in circulating lymphocytes. Therefore, it is thought that while the innate immune system is elevated in pregnancy, the adaptive immune system may be downregulated [11]. Furthermore, the molecular mimicry mechanism describes how a foreign antigen shares sequences with self-antigens, activating T-cells through T-cell receptors and leading to an autoimmune process [12]. Therefore, it is possible that the patient highlighted in this case had a viral trigger coupled with the downregulation of the adaptive immune response leading to an autoimmune reaction and clinical manifestation of autoimmune adrenal insufficiency.
The patient in this case continued her thyroid hormone supplement and oral glucocorticoid for the remainder of her pregnancy. She went on to have a term, vaginal delivery at 38 + 2 weeks of gestation productive of a viable male newborn after presenting in spontaneous labor. She received stress-dose steroids during her labor course and remained hemodynamically stable throughout her intrapartum and postpartum stay. Her follow-up and long-term management plans are to continue titrating her thyroid hormone and glucocorticoid doses per endocrinology recommendations as well as assessing if she is still affected by her adrenal insufficiency and hypothyroidism in the nonpregnant state.
In summary, the diagnosis of adrenal insufficiency, and subsequently adrenal crisis, is difficult to diagnose given vague and overlapping signs and symptoms and the rarity at which it occurs. However, prompt diagnosis is critical in preventing significant maternal and fetal morbidity and mortality.
4 Conclusion
This patient continued her pregnancy on daily oral glucocorticoids and was discharged home with an “emergency Addison's kit” of intramuscular glucocorticoid for sick days, in order to prevent a second episode of adrenal crisis. She progressed to have an uncomplicated, term, spontaneous vaginal delivery with stress-dose steroids, which remains the recommendation in patients on glucocorticoids for adrenal dysfunction [5]. This case highlights the rarity of adrenal crisis in pregnancy, especially in patients with no known history of pre-existing adrenal dysfunction. Importantly, this case also highlights the low suspicion of adrenal insufficiency in pregnancy due to generalized and common symptoms of pregnancy. In this patient's case, it is theorized that she had a predisposition to autoimmune adrenal and thyroid dysfunction that was triggered by an upper respiratory virus, which is a common trigger for autoimmune conditions. While impossible to retrospectively diagnose, this patient may have had more mild symptoms of adrenal insufficiency in her prior pregnancies, as well. In summary, we recommend an increased level of suspicion of adrenal crisis and/or insufficiency in pregnancy in patients like the patient described in this case who have symptoms and lab findings out of proportion to their gestational age or expected severity.
Contributors
Rene MacKinnon participated in acquisition of data and drafted the article.
Allison Eubanks participated in acquisition of data and assisted in drafting the article.
Kelly Shay participated in acquisition of data and assisted in drafting the article.
Brian Belson participated in critical revision of the article for important content.
All authors saw and approved the final version.
The views expressed herein are those of the authors and do not reflect the official views of the Department of the Air Force, the Department of the Army, the Department of the Navy, the Department of Defense, or the United States government.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding was sought or secured in relation to this case report.
Patient Consent
Written informed consent was obtained from the patient for the publication of this case report.
Provenance and Peer Review
This case report was peer reviewed. | DEXTROSE, HYDROCORTISONE | DrugsGivenReaction | CC BY-NC-ND | 33376678 | 19,440,671 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | Diagnosing and managing adrenal crisis in pregnancy: A case report.
The diagnosis of adrenal insufficiency in pregnancy is relatively rare. Further, making this diagnosis can be challenging as many of the symptoms overlap with normal symptoms of pregnancy. Given the potential for severe maternal and fetal morbidity and mortality, early recognition and prompt comprehensive treatment are critical.
A 24-year-old woman, G3 P2002, at 17 + 1 weeks of gestation with unremarkable prenatal course was admitted to hospital for hyperemesis gravidarum in the setting of parainfluenza with a notable blood glucose of 20 mg/dL. On hospital day two, she was transferred to intensive care after developing significant hypotension, hyponatremia, and a new finding of hypothyroidism. During her evaluation in the ICU, she was diagnosed with adrenal crisis and she showed significant improvement with glucocorticoid therapy.
There is a paucity of literature regarding diagnosing adrenal insufficiency in pregnancy. Adrenal crisis in pregnancy can present with symptoms similar to severe nausea and vomiting of pregnancy or hyperemesis gravidarum. Additionally, several critical laboratory tests to support the proper diagnosis require time that acute patients cannot always afford. In this patient's case, the diagnosis was made empirically with improvement after glucocorticoid administration, and was later confirmed by laboratory testing. This case highlights the importance of including adrenal insufficiency in the differential diagnosis of hyperemesis patients in order to quickly manage and treat these often acutely and severely ill patients.
1 Introduction
The adrenal cortex takes part in steroidogenesis, producing glucocorticoids, and androgen precursors. An understanding of the hypothalamic-pituitary-adrenal (HPA) axis aids in understanding the pathophysiology of adrenal disorders. In response to stressors, the hypothalamus makes and secretes corticotopin-releasing hormone (CRH), which then binds to receptors on the anterior pituitary, releasing adrenocorticotropic hormone (ACTH) into circulation. This ACTH then binds to receptors on the adrenal cortex to induce synthesis of glucocorticoids. Cortisol is the major glucocorticoid, and increases in response to stress, which activates the HPA axis. Therefore, all of its functions can be thought to allow the body to function at an increased level of physiologic stress. There are several opportunities for pathologic dysfunction through this complex system, including primary, secondary, or tertiary causes of adrenal disorders [1,2].
The fetoplacental unit plays a major role in cortisol levels in pregnancy [3]. In women with intact adrenal function, the plasma levels of free cortisol, CRH, and cortisol-binding globulin all increase in pregnancy [4]. These hormone levels increase with increasing gestational age. When comparing elevations in maternal total serum cortisol levels to those in non-pregnant controls, a mean increase of 1.3, 2.0 and 2.4 times the normal were found in the 1st, 2nd, and 3rd trimester, respectively [5]. These total and free cortisol level increases are thought to be due to increases in CRH and ACTH from the placenta. Even with these average increases in cortisol levels, the amplitude is poorly understood, and exact reference values have yet to be established [3]. With this brief review, this case highlights a rare case of adrenal crisis developing in pregnancy in a patient with no known history of adrenal dysfunction.
2 Case
A 24-year-old woman, gravida 3 para 2, at 17 = +1 weeks of gestation presented to an acute care center for persistent nausea and vomiting that had begun earlier that morning. Her prenatal course was previously complicated by mild nausea and vomiting of pregnancy. On arrival, she reported lightheadedness and there was concern for confusion and altered mental status by the provider who initially evaluated her. Her vitals were notable for blood pressures in the 100 s/60s and mild tachycardia to the low 100 beats per minute. Notably, a fingerstick blood glucose level was collected given her altered mental status and was found to be 20 mg/dL. She was immediately resuscitated with intravenous fluids with dextrose and antiemetics, with rapid improvement of her blood glucose levels, mental status, and overall symptomatology. She was then transferred for inpatient management and monitoring.
On arrival at the inpatient floor, the patient reported overall improvement. Her blood pressures and symptoms then remained stable overnight. Her review of systems was positive for new-onset nasal congestion, rhinitis, and cough that had begun the same morning as her presenting symptoms of nausea and vomiting. The patient revealed in interview that on several occasions in her prior pregnancies, she had low blood glucose levels associated with nausea and vomiting, requiring intravenous glucose. Her past medical history was significant for mild, intermittent asthma, anemia, and allergic rhinitis and her obstetric history included two prior term, uncomplicated, spontaneous vaginal deliveries. Her family history was notable for a diagnosis of systemic lupus erythematosus in her father.
After initial stabilization, patient developed hypotension with tachycardia despite resuscitation with 2 l of crystalloid fluids, and recurrence of her hypoglycemia without nausea or vomiting. Her rapid viral panel had also resulted by this time positive for parainfluenza virus and her thyroid stimulating hormone had also resulted significant for new hypothyroidism. A rapid response was initiated, and the patient was transferred to the intensive care unit for resuscitation.
On arrival, the critical care team was concerned for adrenal crisis after a trigger from an upper respiratory virus. She was started on intravenous hydrocortisone with immediate improvement in maternal status. She remained stable through the remainder of her hospital stay with regular fetal heart rate checks. Endocrinology assessed this patient and believed she was experiencing adrenal crisis of unknown etiology, potentially secondary to an autoimmune process as supported by several laboratory values collected during her evaluation. In particular, her cortisol level was collected immediately prior to empiric treatment and was found to be 0.5 μg/dL. Additionally, her thyroglobulin antibody level was elevated, consistent with an autoimmune disease process of the thyroid. Finally, her adrenocorticotropin hormone was undetectable on several lab assays, and her prolactin level was 17 μg/L, which is inappropriately low in pregnancy. Her diagnosis of adrenal crisis was supported with immediate improvement with glucocorticoids and a brain MRI that showed a partially empty sella with flattened pituitary gland (Fig. 1), which, although not diagnostic of secondary adrenal dysfunction, can be associated with impairment.Fig. 1 Brain MRI highlighting a partially empty sella (arrow) and flattened pituitary gland.
Fig. 1
3 Discussion
Adrenal insufficiency is defined as the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids. This can be potentially life-threatening, as adrenal physiology is critical in hemodynamic and electrolyte homeostasis. The diagnosis of adrenal insufficiency is based on low morning cortisol concentrations, and this diagnosis is most likely when cortisol is <5 μg/dL [6]. Standard cortisol values are poorly established in pregnancy, and while cortisol is expected to rise with increasing gestational age, reference values in pregnancy have yet to be established [5]. Additionally, an abnormal rise in cortisol levels after a stimulation test of 250 micrograms of cosyntropin can be used to diagnose adrenal insufficiency in pregnancy, for which the minimum expected peak values per trimester are 25, 29, and 32 μg/dL, respectively [5,7].
The majority of adrenal insufficiency cases during pregnancy are diagnosed prior to conception. There is typically a low clinical suspicion of new adrenal insufficiency in pregnancy, given the overlapping signs of symptoms with normal pregnancy, nausea and vomiting in pregnancy, and hyperemesis gravidarum such as fatigue, nausea, vomiting, and mild hypotension [7]. In fact, only 100 cases of adrenal insufficiency have been reported to be diagnosed during pregnancy [8].
Adrenal crisis is an acute form of adrenal insufficiency leading to hemodynamic instability, typically necessitating care in an intensive care unit and immediate intravenous glucocorticoids. When a patient progresses to adrenal crisis, timing often does not allow for cosyntropin or other testing to diagnose adrenal insufficiency, as treating empirically is far more important, as was the case with this patient. Although rare, adrenal crisis is critical to diagnose quickly, as the mortality rate without treatment ranges as high as 35%–45%. Additionally, severe maternal and fetal morbidity of untreated adrenal crisis includes poor wound healing, infection, venous thromboembolism, prolonged hospital stays, fetal intrauterine growth restriction, preterm delivery, and increased risk of Cesarean delivery [3,7]. Even in patients with a known history of adrenal insufficiency in pregnancy, the development of adrenal crisis is rare. In a prospective series of 423 patients with adrenal insufficiency, pregnancy was found to trigger adrenal crisis in 0.2%. In a study of 93 patients with known insufficiency, only 1.1% developed adrenal crisis in pregnancy. The incidence of new-onset adrenal crisis without a known pre-existing adrenal disorder is unknown [7].
As mentioned in the case, this patient's cortisol levels were low and ACTH levels were undetectable on separate laboratory draws. Typically, ACTH increases in proportion to increasing cortisol in pregnancy. While standard average values are poorly established, ACTH has been documented to range anywhere from 10 to 300 pg/mL between 10 and 40 weeks of gestation, respectively [9]. Additionally, her thyroid stimulating hormone was decreased with an increased thyroglobulin antibody, consistent with autoimmune involvement. Finally, her prolactin was within normal range for a nonpregnant woman, which is unusual, as prolactin is typically elevated in pregnancy, ranging from 35 to 600 ng/mL, with increases seen with increasing gestational age [10].
While the trigger of this patient's adrenal insufficiency is unclear, downregulation of the immune system during pregnancy coupled with her acute parainfluenza virus may have contributed to the possible autoimmune process in this case. The maternal immune system is complex in pregnancy. There is evidence that pregnancy causes generalized leukocyte activation with an increase in circulating granulocytes and a decrease in circulating lymphocytes. Therefore, it is thought that while the innate immune system is elevated in pregnancy, the adaptive immune system may be downregulated [11]. Furthermore, the molecular mimicry mechanism describes how a foreign antigen shares sequences with self-antigens, activating T-cells through T-cell receptors and leading to an autoimmune process [12]. Therefore, it is possible that the patient highlighted in this case had a viral trigger coupled with the downregulation of the adaptive immune response leading to an autoimmune reaction and clinical manifestation of autoimmune adrenal insufficiency.
The patient in this case continued her thyroid hormone supplement and oral glucocorticoid for the remainder of her pregnancy. She went on to have a term, vaginal delivery at 38 + 2 weeks of gestation productive of a viable male newborn after presenting in spontaneous labor. She received stress-dose steroids during her labor course and remained hemodynamically stable throughout her intrapartum and postpartum stay. Her follow-up and long-term management plans are to continue titrating her thyroid hormone and glucocorticoid doses per endocrinology recommendations as well as assessing if she is still affected by her adrenal insufficiency and hypothyroidism in the nonpregnant state.
In summary, the diagnosis of adrenal insufficiency, and subsequently adrenal crisis, is difficult to diagnose given vague and overlapping signs and symptoms and the rarity at which it occurs. However, prompt diagnosis is critical in preventing significant maternal and fetal morbidity and mortality.
4 Conclusion
This patient continued her pregnancy on daily oral glucocorticoids and was discharged home with an “emergency Addison's kit” of intramuscular glucocorticoid for sick days, in order to prevent a second episode of adrenal crisis. She progressed to have an uncomplicated, term, spontaneous vaginal delivery with stress-dose steroids, which remains the recommendation in patients on glucocorticoids for adrenal dysfunction [5]. This case highlights the rarity of adrenal crisis in pregnancy, especially in patients with no known history of pre-existing adrenal dysfunction. Importantly, this case also highlights the low suspicion of adrenal insufficiency in pregnancy due to generalized and common symptoms of pregnancy. In this patient's case, it is theorized that she had a predisposition to autoimmune adrenal and thyroid dysfunction that was triggered by an upper respiratory virus, which is a common trigger for autoimmune conditions. While impossible to retrospectively diagnose, this patient may have had more mild symptoms of adrenal insufficiency in her prior pregnancies, as well. In summary, we recommend an increased level of suspicion of adrenal crisis and/or insufficiency in pregnancy in patients like the patient described in this case who have symptoms and lab findings out of proportion to their gestational age or expected severity.
Contributors
Rene MacKinnon participated in acquisition of data and drafted the article.
Allison Eubanks participated in acquisition of data and assisted in drafting the article.
Kelly Shay participated in acquisition of data and assisted in drafting the article.
Brian Belson participated in critical revision of the article for important content.
All authors saw and approved the final version.
The views expressed herein are those of the authors and do not reflect the official views of the Department of the Air Force, the Department of the Army, the Department of the Navy, the Department of Defense, or the United States government.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding was sought or secured in relation to this case report.
Patient Consent
Written informed consent was obtained from the patient for the publication of this case report.
Provenance and Peer Review
This case report was peer reviewed. | DEXTROSE, HYDROCORTISONE | DrugsGivenReaction | CC BY-NC-ND | 33376678 | 19,440,671 | 2021-01 |
What was the administration route of drug 'DEXTROSE'? | Diagnosing and managing adrenal crisis in pregnancy: A case report.
The diagnosis of adrenal insufficiency in pregnancy is relatively rare. Further, making this diagnosis can be challenging as many of the symptoms overlap with normal symptoms of pregnancy. Given the potential for severe maternal and fetal morbidity and mortality, early recognition and prompt comprehensive treatment are critical.
A 24-year-old woman, G3 P2002, at 17 + 1 weeks of gestation with unremarkable prenatal course was admitted to hospital for hyperemesis gravidarum in the setting of parainfluenza with a notable blood glucose of 20 mg/dL. On hospital day two, she was transferred to intensive care after developing significant hypotension, hyponatremia, and a new finding of hypothyroidism. During her evaluation in the ICU, she was diagnosed with adrenal crisis and she showed significant improvement with glucocorticoid therapy.
There is a paucity of literature regarding diagnosing adrenal insufficiency in pregnancy. Adrenal crisis in pregnancy can present with symptoms similar to severe nausea and vomiting of pregnancy or hyperemesis gravidarum. Additionally, several critical laboratory tests to support the proper diagnosis require time that acute patients cannot always afford. In this patient's case, the diagnosis was made empirically with improvement after glucocorticoid administration, and was later confirmed by laboratory testing. This case highlights the importance of including adrenal insufficiency in the differential diagnosis of hyperemesis patients in order to quickly manage and treat these often acutely and severely ill patients.
1 Introduction
The adrenal cortex takes part in steroidogenesis, producing glucocorticoids, and androgen precursors. An understanding of the hypothalamic-pituitary-adrenal (HPA) axis aids in understanding the pathophysiology of adrenal disorders. In response to stressors, the hypothalamus makes and secretes corticotopin-releasing hormone (CRH), which then binds to receptors on the anterior pituitary, releasing adrenocorticotropic hormone (ACTH) into circulation. This ACTH then binds to receptors on the adrenal cortex to induce synthesis of glucocorticoids. Cortisol is the major glucocorticoid, and increases in response to stress, which activates the HPA axis. Therefore, all of its functions can be thought to allow the body to function at an increased level of physiologic stress. There are several opportunities for pathologic dysfunction through this complex system, including primary, secondary, or tertiary causes of adrenal disorders [1,2].
The fetoplacental unit plays a major role in cortisol levels in pregnancy [3]. In women with intact adrenal function, the plasma levels of free cortisol, CRH, and cortisol-binding globulin all increase in pregnancy [4]. These hormone levels increase with increasing gestational age. When comparing elevations in maternal total serum cortisol levels to those in non-pregnant controls, a mean increase of 1.3, 2.0 and 2.4 times the normal were found in the 1st, 2nd, and 3rd trimester, respectively [5]. These total and free cortisol level increases are thought to be due to increases in CRH and ACTH from the placenta. Even with these average increases in cortisol levels, the amplitude is poorly understood, and exact reference values have yet to be established [3]. With this brief review, this case highlights a rare case of adrenal crisis developing in pregnancy in a patient with no known history of adrenal dysfunction.
2 Case
A 24-year-old woman, gravida 3 para 2, at 17 = +1 weeks of gestation presented to an acute care center for persistent nausea and vomiting that had begun earlier that morning. Her prenatal course was previously complicated by mild nausea and vomiting of pregnancy. On arrival, she reported lightheadedness and there was concern for confusion and altered mental status by the provider who initially evaluated her. Her vitals were notable for blood pressures in the 100 s/60s and mild tachycardia to the low 100 beats per minute. Notably, a fingerstick blood glucose level was collected given her altered mental status and was found to be 20 mg/dL. She was immediately resuscitated with intravenous fluids with dextrose and antiemetics, with rapid improvement of her blood glucose levels, mental status, and overall symptomatology. She was then transferred for inpatient management and monitoring.
On arrival at the inpatient floor, the patient reported overall improvement. Her blood pressures and symptoms then remained stable overnight. Her review of systems was positive for new-onset nasal congestion, rhinitis, and cough that had begun the same morning as her presenting symptoms of nausea and vomiting. The patient revealed in interview that on several occasions in her prior pregnancies, she had low blood glucose levels associated with nausea and vomiting, requiring intravenous glucose. Her past medical history was significant for mild, intermittent asthma, anemia, and allergic rhinitis and her obstetric history included two prior term, uncomplicated, spontaneous vaginal deliveries. Her family history was notable for a diagnosis of systemic lupus erythematosus in her father.
After initial stabilization, patient developed hypotension with tachycardia despite resuscitation with 2 l of crystalloid fluids, and recurrence of her hypoglycemia without nausea or vomiting. Her rapid viral panel had also resulted by this time positive for parainfluenza virus and her thyroid stimulating hormone had also resulted significant for new hypothyroidism. A rapid response was initiated, and the patient was transferred to the intensive care unit for resuscitation.
On arrival, the critical care team was concerned for adrenal crisis after a trigger from an upper respiratory virus. She was started on intravenous hydrocortisone with immediate improvement in maternal status. She remained stable through the remainder of her hospital stay with regular fetal heart rate checks. Endocrinology assessed this patient and believed she was experiencing adrenal crisis of unknown etiology, potentially secondary to an autoimmune process as supported by several laboratory values collected during her evaluation. In particular, her cortisol level was collected immediately prior to empiric treatment and was found to be 0.5 μg/dL. Additionally, her thyroglobulin antibody level was elevated, consistent with an autoimmune disease process of the thyroid. Finally, her adrenocorticotropin hormone was undetectable on several lab assays, and her prolactin level was 17 μg/L, which is inappropriately low in pregnancy. Her diagnosis of adrenal crisis was supported with immediate improvement with glucocorticoids and a brain MRI that showed a partially empty sella with flattened pituitary gland (Fig. 1), which, although not diagnostic of secondary adrenal dysfunction, can be associated with impairment.Fig. 1 Brain MRI highlighting a partially empty sella (arrow) and flattened pituitary gland.
Fig. 1
3 Discussion
Adrenal insufficiency is defined as the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids. This can be potentially life-threatening, as adrenal physiology is critical in hemodynamic and electrolyte homeostasis. The diagnosis of adrenal insufficiency is based on low morning cortisol concentrations, and this diagnosis is most likely when cortisol is <5 μg/dL [6]. Standard cortisol values are poorly established in pregnancy, and while cortisol is expected to rise with increasing gestational age, reference values in pregnancy have yet to be established [5]. Additionally, an abnormal rise in cortisol levels after a stimulation test of 250 micrograms of cosyntropin can be used to diagnose adrenal insufficiency in pregnancy, for which the minimum expected peak values per trimester are 25, 29, and 32 μg/dL, respectively [5,7].
The majority of adrenal insufficiency cases during pregnancy are diagnosed prior to conception. There is typically a low clinical suspicion of new adrenal insufficiency in pregnancy, given the overlapping signs of symptoms with normal pregnancy, nausea and vomiting in pregnancy, and hyperemesis gravidarum such as fatigue, nausea, vomiting, and mild hypotension [7]. In fact, only 100 cases of adrenal insufficiency have been reported to be diagnosed during pregnancy [8].
Adrenal crisis is an acute form of adrenal insufficiency leading to hemodynamic instability, typically necessitating care in an intensive care unit and immediate intravenous glucocorticoids. When a patient progresses to adrenal crisis, timing often does not allow for cosyntropin or other testing to diagnose adrenal insufficiency, as treating empirically is far more important, as was the case with this patient. Although rare, adrenal crisis is critical to diagnose quickly, as the mortality rate without treatment ranges as high as 35%–45%. Additionally, severe maternal and fetal morbidity of untreated adrenal crisis includes poor wound healing, infection, venous thromboembolism, prolonged hospital stays, fetal intrauterine growth restriction, preterm delivery, and increased risk of Cesarean delivery [3,7]. Even in patients with a known history of adrenal insufficiency in pregnancy, the development of adrenal crisis is rare. In a prospective series of 423 patients with adrenal insufficiency, pregnancy was found to trigger adrenal crisis in 0.2%. In a study of 93 patients with known insufficiency, only 1.1% developed adrenal crisis in pregnancy. The incidence of new-onset adrenal crisis without a known pre-existing adrenal disorder is unknown [7].
As mentioned in the case, this patient's cortisol levels were low and ACTH levels were undetectable on separate laboratory draws. Typically, ACTH increases in proportion to increasing cortisol in pregnancy. While standard average values are poorly established, ACTH has been documented to range anywhere from 10 to 300 pg/mL between 10 and 40 weeks of gestation, respectively [9]. Additionally, her thyroid stimulating hormone was decreased with an increased thyroglobulin antibody, consistent with autoimmune involvement. Finally, her prolactin was within normal range for a nonpregnant woman, which is unusual, as prolactin is typically elevated in pregnancy, ranging from 35 to 600 ng/mL, with increases seen with increasing gestational age [10].
While the trigger of this patient's adrenal insufficiency is unclear, downregulation of the immune system during pregnancy coupled with her acute parainfluenza virus may have contributed to the possible autoimmune process in this case. The maternal immune system is complex in pregnancy. There is evidence that pregnancy causes generalized leukocyte activation with an increase in circulating granulocytes and a decrease in circulating lymphocytes. Therefore, it is thought that while the innate immune system is elevated in pregnancy, the adaptive immune system may be downregulated [11]. Furthermore, the molecular mimicry mechanism describes how a foreign antigen shares sequences with self-antigens, activating T-cells through T-cell receptors and leading to an autoimmune process [12]. Therefore, it is possible that the patient highlighted in this case had a viral trigger coupled with the downregulation of the adaptive immune response leading to an autoimmune reaction and clinical manifestation of autoimmune adrenal insufficiency.
The patient in this case continued her thyroid hormone supplement and oral glucocorticoid for the remainder of her pregnancy. She went on to have a term, vaginal delivery at 38 + 2 weeks of gestation productive of a viable male newborn after presenting in spontaneous labor. She received stress-dose steroids during her labor course and remained hemodynamically stable throughout her intrapartum and postpartum stay. Her follow-up and long-term management plans are to continue titrating her thyroid hormone and glucocorticoid doses per endocrinology recommendations as well as assessing if she is still affected by her adrenal insufficiency and hypothyroidism in the nonpregnant state.
In summary, the diagnosis of adrenal insufficiency, and subsequently adrenal crisis, is difficult to diagnose given vague and overlapping signs and symptoms and the rarity at which it occurs. However, prompt diagnosis is critical in preventing significant maternal and fetal morbidity and mortality.
4 Conclusion
This patient continued her pregnancy on daily oral glucocorticoids and was discharged home with an “emergency Addison's kit” of intramuscular glucocorticoid for sick days, in order to prevent a second episode of adrenal crisis. She progressed to have an uncomplicated, term, spontaneous vaginal delivery with stress-dose steroids, which remains the recommendation in patients on glucocorticoids for adrenal dysfunction [5]. This case highlights the rarity of adrenal crisis in pregnancy, especially in patients with no known history of pre-existing adrenal dysfunction. Importantly, this case also highlights the low suspicion of adrenal insufficiency in pregnancy due to generalized and common symptoms of pregnancy. In this patient's case, it is theorized that she had a predisposition to autoimmune adrenal and thyroid dysfunction that was triggered by an upper respiratory virus, which is a common trigger for autoimmune conditions. While impossible to retrospectively diagnose, this patient may have had more mild symptoms of adrenal insufficiency in her prior pregnancies, as well. In summary, we recommend an increased level of suspicion of adrenal crisis and/or insufficiency in pregnancy in patients like the patient described in this case who have symptoms and lab findings out of proportion to their gestational age or expected severity.
Contributors
Rene MacKinnon participated in acquisition of data and drafted the article.
Allison Eubanks participated in acquisition of data and assisted in drafting the article.
Kelly Shay participated in acquisition of data and assisted in drafting the article.
Brian Belson participated in critical revision of the article for important content.
All authors saw and approved the final version.
The views expressed herein are those of the authors and do not reflect the official views of the Department of the Air Force, the Department of the Army, the Department of the Navy, the Department of Defense, or the United States government.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding was sought or secured in relation to this case report.
Patient Consent
Written informed consent was obtained from the patient for the publication of this case report.
Provenance and Peer Review
This case report was peer reviewed. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376678 | 19,440,671 | 2021-01 |
What was the administration route of drug 'HYDROCORTISONE'? | Diagnosing and managing adrenal crisis in pregnancy: A case report.
The diagnosis of adrenal insufficiency in pregnancy is relatively rare. Further, making this diagnosis can be challenging as many of the symptoms overlap with normal symptoms of pregnancy. Given the potential for severe maternal and fetal morbidity and mortality, early recognition and prompt comprehensive treatment are critical.
A 24-year-old woman, G3 P2002, at 17 + 1 weeks of gestation with unremarkable prenatal course was admitted to hospital for hyperemesis gravidarum in the setting of parainfluenza with a notable blood glucose of 20 mg/dL. On hospital day two, she was transferred to intensive care after developing significant hypotension, hyponatremia, and a new finding of hypothyroidism. During her evaluation in the ICU, she was diagnosed with adrenal crisis and she showed significant improvement with glucocorticoid therapy.
There is a paucity of literature regarding diagnosing adrenal insufficiency in pregnancy. Adrenal crisis in pregnancy can present with symptoms similar to severe nausea and vomiting of pregnancy or hyperemesis gravidarum. Additionally, several critical laboratory tests to support the proper diagnosis require time that acute patients cannot always afford. In this patient's case, the diagnosis was made empirically with improvement after glucocorticoid administration, and was later confirmed by laboratory testing. This case highlights the importance of including adrenal insufficiency in the differential diagnosis of hyperemesis patients in order to quickly manage and treat these often acutely and severely ill patients.
1 Introduction
The adrenal cortex takes part in steroidogenesis, producing glucocorticoids, and androgen precursors. An understanding of the hypothalamic-pituitary-adrenal (HPA) axis aids in understanding the pathophysiology of adrenal disorders. In response to stressors, the hypothalamus makes and secretes corticotopin-releasing hormone (CRH), which then binds to receptors on the anterior pituitary, releasing adrenocorticotropic hormone (ACTH) into circulation. This ACTH then binds to receptors on the adrenal cortex to induce synthesis of glucocorticoids. Cortisol is the major glucocorticoid, and increases in response to stress, which activates the HPA axis. Therefore, all of its functions can be thought to allow the body to function at an increased level of physiologic stress. There are several opportunities for pathologic dysfunction through this complex system, including primary, secondary, or tertiary causes of adrenal disorders [1,2].
The fetoplacental unit plays a major role in cortisol levels in pregnancy [3]. In women with intact adrenal function, the plasma levels of free cortisol, CRH, and cortisol-binding globulin all increase in pregnancy [4]. These hormone levels increase with increasing gestational age. When comparing elevations in maternal total serum cortisol levels to those in non-pregnant controls, a mean increase of 1.3, 2.0 and 2.4 times the normal were found in the 1st, 2nd, and 3rd trimester, respectively [5]. These total and free cortisol level increases are thought to be due to increases in CRH and ACTH from the placenta. Even with these average increases in cortisol levels, the amplitude is poorly understood, and exact reference values have yet to be established [3]. With this brief review, this case highlights a rare case of adrenal crisis developing in pregnancy in a patient with no known history of adrenal dysfunction.
2 Case
A 24-year-old woman, gravida 3 para 2, at 17 = +1 weeks of gestation presented to an acute care center for persistent nausea and vomiting that had begun earlier that morning. Her prenatal course was previously complicated by mild nausea and vomiting of pregnancy. On arrival, she reported lightheadedness and there was concern for confusion and altered mental status by the provider who initially evaluated her. Her vitals were notable for blood pressures in the 100 s/60s and mild tachycardia to the low 100 beats per minute. Notably, a fingerstick blood glucose level was collected given her altered mental status and was found to be 20 mg/dL. She was immediately resuscitated with intravenous fluids with dextrose and antiemetics, with rapid improvement of her blood glucose levels, mental status, and overall symptomatology. She was then transferred for inpatient management and monitoring.
On arrival at the inpatient floor, the patient reported overall improvement. Her blood pressures and symptoms then remained stable overnight. Her review of systems was positive for new-onset nasal congestion, rhinitis, and cough that had begun the same morning as her presenting symptoms of nausea and vomiting. The patient revealed in interview that on several occasions in her prior pregnancies, she had low blood glucose levels associated with nausea and vomiting, requiring intravenous glucose. Her past medical history was significant for mild, intermittent asthma, anemia, and allergic rhinitis and her obstetric history included two prior term, uncomplicated, spontaneous vaginal deliveries. Her family history was notable for a diagnosis of systemic lupus erythematosus in her father.
After initial stabilization, patient developed hypotension with tachycardia despite resuscitation with 2 l of crystalloid fluids, and recurrence of her hypoglycemia without nausea or vomiting. Her rapid viral panel had also resulted by this time positive for parainfluenza virus and her thyroid stimulating hormone had also resulted significant for new hypothyroidism. A rapid response was initiated, and the patient was transferred to the intensive care unit for resuscitation.
On arrival, the critical care team was concerned for adrenal crisis after a trigger from an upper respiratory virus. She was started on intravenous hydrocortisone with immediate improvement in maternal status. She remained stable through the remainder of her hospital stay with regular fetal heart rate checks. Endocrinology assessed this patient and believed she was experiencing adrenal crisis of unknown etiology, potentially secondary to an autoimmune process as supported by several laboratory values collected during her evaluation. In particular, her cortisol level was collected immediately prior to empiric treatment and was found to be 0.5 μg/dL. Additionally, her thyroglobulin antibody level was elevated, consistent with an autoimmune disease process of the thyroid. Finally, her adrenocorticotropin hormone was undetectable on several lab assays, and her prolactin level was 17 μg/L, which is inappropriately low in pregnancy. Her diagnosis of adrenal crisis was supported with immediate improvement with glucocorticoids and a brain MRI that showed a partially empty sella with flattened pituitary gland (Fig. 1), which, although not diagnostic of secondary adrenal dysfunction, can be associated with impairment.Fig. 1 Brain MRI highlighting a partially empty sella (arrow) and flattened pituitary gland.
Fig. 1
3 Discussion
Adrenal insufficiency is defined as the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids. This can be potentially life-threatening, as adrenal physiology is critical in hemodynamic and electrolyte homeostasis. The diagnosis of adrenal insufficiency is based on low morning cortisol concentrations, and this diagnosis is most likely when cortisol is <5 μg/dL [6]. Standard cortisol values are poorly established in pregnancy, and while cortisol is expected to rise with increasing gestational age, reference values in pregnancy have yet to be established [5]. Additionally, an abnormal rise in cortisol levels after a stimulation test of 250 micrograms of cosyntropin can be used to diagnose adrenal insufficiency in pregnancy, for which the minimum expected peak values per trimester are 25, 29, and 32 μg/dL, respectively [5,7].
The majority of adrenal insufficiency cases during pregnancy are diagnosed prior to conception. There is typically a low clinical suspicion of new adrenal insufficiency in pregnancy, given the overlapping signs of symptoms with normal pregnancy, nausea and vomiting in pregnancy, and hyperemesis gravidarum such as fatigue, nausea, vomiting, and mild hypotension [7]. In fact, only 100 cases of adrenal insufficiency have been reported to be diagnosed during pregnancy [8].
Adrenal crisis is an acute form of adrenal insufficiency leading to hemodynamic instability, typically necessitating care in an intensive care unit and immediate intravenous glucocorticoids. When a patient progresses to adrenal crisis, timing often does not allow for cosyntropin or other testing to diagnose adrenal insufficiency, as treating empirically is far more important, as was the case with this patient. Although rare, adrenal crisis is critical to diagnose quickly, as the mortality rate without treatment ranges as high as 35%–45%. Additionally, severe maternal and fetal morbidity of untreated adrenal crisis includes poor wound healing, infection, venous thromboembolism, prolonged hospital stays, fetal intrauterine growth restriction, preterm delivery, and increased risk of Cesarean delivery [3,7]. Even in patients with a known history of adrenal insufficiency in pregnancy, the development of adrenal crisis is rare. In a prospective series of 423 patients with adrenal insufficiency, pregnancy was found to trigger adrenal crisis in 0.2%. In a study of 93 patients with known insufficiency, only 1.1% developed adrenal crisis in pregnancy. The incidence of new-onset adrenal crisis without a known pre-existing adrenal disorder is unknown [7].
As mentioned in the case, this patient's cortisol levels were low and ACTH levels were undetectable on separate laboratory draws. Typically, ACTH increases in proportion to increasing cortisol in pregnancy. While standard average values are poorly established, ACTH has been documented to range anywhere from 10 to 300 pg/mL between 10 and 40 weeks of gestation, respectively [9]. Additionally, her thyroid stimulating hormone was decreased with an increased thyroglobulin antibody, consistent with autoimmune involvement. Finally, her prolactin was within normal range for a nonpregnant woman, which is unusual, as prolactin is typically elevated in pregnancy, ranging from 35 to 600 ng/mL, with increases seen with increasing gestational age [10].
While the trigger of this patient's adrenal insufficiency is unclear, downregulation of the immune system during pregnancy coupled with her acute parainfluenza virus may have contributed to the possible autoimmune process in this case. The maternal immune system is complex in pregnancy. There is evidence that pregnancy causes generalized leukocyte activation with an increase in circulating granulocytes and a decrease in circulating lymphocytes. Therefore, it is thought that while the innate immune system is elevated in pregnancy, the adaptive immune system may be downregulated [11]. Furthermore, the molecular mimicry mechanism describes how a foreign antigen shares sequences with self-antigens, activating T-cells through T-cell receptors and leading to an autoimmune process [12]. Therefore, it is possible that the patient highlighted in this case had a viral trigger coupled with the downregulation of the adaptive immune response leading to an autoimmune reaction and clinical manifestation of autoimmune adrenal insufficiency.
The patient in this case continued her thyroid hormone supplement and oral glucocorticoid for the remainder of her pregnancy. She went on to have a term, vaginal delivery at 38 + 2 weeks of gestation productive of a viable male newborn after presenting in spontaneous labor. She received stress-dose steroids during her labor course and remained hemodynamically stable throughout her intrapartum and postpartum stay. Her follow-up and long-term management plans are to continue titrating her thyroid hormone and glucocorticoid doses per endocrinology recommendations as well as assessing if she is still affected by her adrenal insufficiency and hypothyroidism in the nonpregnant state.
In summary, the diagnosis of adrenal insufficiency, and subsequently adrenal crisis, is difficult to diagnose given vague and overlapping signs and symptoms and the rarity at which it occurs. However, prompt diagnosis is critical in preventing significant maternal and fetal morbidity and mortality.
4 Conclusion
This patient continued her pregnancy on daily oral glucocorticoids and was discharged home with an “emergency Addison's kit” of intramuscular glucocorticoid for sick days, in order to prevent a second episode of adrenal crisis. She progressed to have an uncomplicated, term, spontaneous vaginal delivery with stress-dose steroids, which remains the recommendation in patients on glucocorticoids for adrenal dysfunction [5]. This case highlights the rarity of adrenal crisis in pregnancy, especially in patients with no known history of pre-existing adrenal dysfunction. Importantly, this case also highlights the low suspicion of adrenal insufficiency in pregnancy due to generalized and common symptoms of pregnancy. In this patient's case, it is theorized that she had a predisposition to autoimmune adrenal and thyroid dysfunction that was triggered by an upper respiratory virus, which is a common trigger for autoimmune conditions. While impossible to retrospectively diagnose, this patient may have had more mild symptoms of adrenal insufficiency in her prior pregnancies, as well. In summary, we recommend an increased level of suspicion of adrenal crisis and/or insufficiency in pregnancy in patients like the patient described in this case who have symptoms and lab findings out of proportion to their gestational age or expected severity.
Contributors
Rene MacKinnon participated in acquisition of data and drafted the article.
Allison Eubanks participated in acquisition of data and assisted in drafting the article.
Kelly Shay participated in acquisition of data and assisted in drafting the article.
Brian Belson participated in critical revision of the article for important content.
All authors saw and approved the final version.
The views expressed herein are those of the authors and do not reflect the official views of the Department of the Air Force, the Department of the Army, the Department of the Navy, the Department of Defense, or the United States government.
Conflict of Interest
The authors declare that they have no conflict of interest regarding the publication of this case report.
Funding
No funding was sought or secured in relation to this case report.
Patient Consent
Written informed consent was obtained from the patient for the publication of this case report.
Provenance and Peer Review
This case report was peer reviewed. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33376678 | 19,440,671 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adrenal cyst'. | A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.
Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.
Adrenal cysts are rare cystic masses that are detected incidentally during autopsy in 0.06% of the population [1]. Approximately 6% of tumors detected as adrenal incidentalomas are adrenal cysts, as observed from the data of surgical series [2, 3]; however, a recent prospective study clarified that the incidence is much lower (< 1%) [4]. Adrenal cysts are classified as vascular or endothelial, epithelial, or parasitic [1, 5]. Pseudocysts are the most common type of adrenal cysts [6, 7]. Endothelial cysts associated with adrenal neoplasms are rare, with only a few reported cases [6, 8]. In addition, the cases of unilateral endothelial cysts and bilateral adrenal neoplasms have not been reported, to the best of our knowledge.
Primary aldosteronism is caused by the autonomous secretion of aldosterone owing to aldosterone-producing adenoma, multiple adrenocortical micronodules, and diffuse adrenocortical hyperplasia of the zona glomerulosa [9]. These conditions are known to be associated with high serum aldosterone and low renin levels, resulting in hypertension. However, we recently experienced a case of diffuse hyperplasia of the zona glomerulosa, positive for 18-hydroxylase: aldosterone synthase (CYP11β2), in which the patient had normal serum aldosterone levels, renin activity, and blood pressure.
Here, we report a rare case of bilateral adrenal adenomas with unilateral adrenal endothelial cysts. The possibility of sodium-glucose cotransporter protein 2 (SGLT2) inhibitor causing bilateral hyperplasia of the zona glomerulosa of the adrenal gland will also be discussed.
1. Case Presentation
A 65-year-old Japanese woman was referred to our hospital for characterization of the bilateral adrenal incidentaloma. At age 63, the patient was diagnosed with type 2 diabetes, which had been treated with diet and exercise therapy, and a gallstone identified by abdominal ultrasonography at a nearby clinic. Other than the diabetes and gallstone, she did not have any past medical history that needs specific mention. At age 64, the patient was administered an SGLT2 inhibitor, empagliflozin (10 mg/day), without any other medications and underwent abdominal ultrasonography for follow-up of the gallstone; however, adrenal masses were not identified at this point. At age 65, adrenal masses were incidentally identified during the abdominal ultrasonography during the follow-up examination of the gallstone. Consequently, subsequent plain abdominal computed tomography (CT) was performed, which revealed bilateral masses measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side (Fig. 1A). The right-sided mass was flat, with a small high-density spot, and heterogeneous, with a high-density (30-50 Hounsfield units [H]) and a low-density area (10-20 H). The left-sided mass was almost round with a relatively heterogeneous density (10-40 H).
Figure 1. Computed tomography (CT) scans of the right and left adrenal area. A, Plain CT showing a mass on the left and right sides (measuring 6.2 × 2.5 cm and 4.6 × 4.1 cm, respectively). B, Contrast-enhanced CT. C to F, Magnetic resonance imaging (MRI). C and D, T2-weighted images and images E, in phase and F, out of phase using chemical shift MRI.
The patient was admitted to our hospital for detailed examination. On admission, the patient did not present any signs or symptoms associated with excess adrenal cortical hormone levels or its deficiency. She had been taking an antidiabetic drug (empagliflozin, 10 mg/day) for approximately 1 year, and her diabetes was well controlled (fasting blood glucose: 116 mg/dL, glycated hemoglobin [hemoglobin A1c]: 6.9%). Between the third and first month prior to her introduction to our hospital, the patient used an ointment containing betamethasone butyrate propionate (exogenous glucocorticoid) for dermatitis. Physical examination revealed no significant findings. Clinical parameters were as follows: body height, 145.9 cm; body weight, 55.9 kg; blood pressure, 122/60 mm Hg; and heart rate, 60 beats/min. The laboratory data are presented in Table 1. The complete blood count and blood biochemistry tests were almost within the normal range.
Table 1. Laboratory findings of the patient
Peripheral blood Endocrinological data Load test
WBC 6060/mm3 (3300-8600) (Plasma) (CRH load)
RBC 462 × 104/mm3 (386-492) Epinephrine 24 pg/mL (0-100) ACTH 0 min 23.1 pg/mL
Hb 15.0 g/dL (11.6-14.8) Norepinephrine 304 pg/mL (100-450) 30 min 185.9 pg/mL
Ht 44.3% (35.1-44.4) Dopamine 10 pg/mL (0-20) 60 min 155.2 pg/mL
Plt 17.8 × 104/mm3 (15.8-34.8) Renin 2.3 ng/mL/h (0.3-5.4) 90 min 65.6 pg/mL
Aldosterone 149 pg/mL (29.9-159) 120 min 37.3 pg/mL
Biochemical data ARR 65 (< 200) Cortisol 0 min 4.5 μg/dL
T.P. 7.2 g/dL (6.6-8.1) ACTH (06:00) 32.0 pg/mL (7.2-63.3) 30 min 4.8 μg/dL
Albumin 4.2 g/dL (4.1-5.1) (12:00) 10.4 pg/mL 60 min 5.5 μg/dL
T.Bil 0.6 mg/dL (0.4-1.5) (18:00) 12.5 pg/mL 90 min 5.7 μg/dL
AST 25 U/L (13-30) (23:00) 13.6 pg/mL 120 min 5.5 μg/dL
ALT 29 U/L (7-23) Cortisol (06:00) 7.0 μg/dL (6.2-19.4)
LDH 248 U/L (124-222) (12:00) 4.4 μg/dL (ACTH load)
ALP 156 U/L (106-322) (18:00) 3.4 μg/dL Cortisol 0 min 4.3 μg/dL
rGTP 28 U/L (9-32) (23:00) 3.4 μg/dL 30 min 4.5 μg/dL
BUN 13 mg/dL (8-20) DHEA-S 96 μg/dL (12-133) 60 min 5.2 μg/dL
Crea 0.68 mg/dL (0.46-0.79) 90 min 5.7 μg/dL
Na 138 mEq/L (138-145) (Urine) 120 min 6.0 μg/dL
K 4.2 mEq/L (3.6-4.8) Epinephrine 8.2 μg/d (3.4-26.9)
Cl 105 mEq/L (101-108) Norepinephrine 133.3 μg/d (48.6-168.4)
Glucose 116 mg/dL (73-109) Dopamine 800.2 μg/d (365-961.5)
T.chol 177 mg/dL (142-220) Aldosterone 11 μg/d (0-10)
HbA1c 6.9% (4.9-6.2) Cortisol 75.3 μg/d (11.2-80.3)
sIL-2R 325 U/mL (121-613)
Reference ranges are in parentheses.
Abbreviations: ACTH, adrenocorticotropin; ALP, alkaline phosphatase; ALT, alanine transferase; ARR, aldosterone/renin ratio; AST, aspartate transaminase; BUN, blood urea nitrogen; Cl, chlorine; Crea, creatinine; DHEA-S, dehydroepiandrosterone-sulfate; Hb, hemoglobin; HbA1c, glycated hemoglobin; Ht, hematocrit; K, potassium; LDH, lactate dehydrogenase; Na, natrium; Plt, platelets; RBC, red blood cells; rGTP, γ-glutamyl transferase; sIL-2R, soluble interleukin-2 receptor; T.Bil, total bilirubin; T.chol, total cholesterol; T.P, total protein; WBC, white blood cells.
Endocrinological data are also presented in Table 1. Blood and 24-hour urine catecholamines were within the normal range. Plasma aldosterone concentration of 149 pg/mL, plasma renin activity of 2.3 ng/mL/h, and aldosterone/renin ratio of 65 were within the normal range. Urine aldosterone level (11 µg/day) was slightly elevated. Cortisol and adrenocorticotropin (ACTH) levels early in the morning were 5.3 µg/dL and 15.8 pg/mL (at an outpatient clinic) and 7.0 µg/dL and 32.0 pg/mL (after hospitalization), respectively (cortisol and ACTH levels were measured by Eclusys Cortisol II and Eclusys ACTH; reference values were 6.2-19.4 µg/dL and 7.2-63.3 pg/mL, respectively [Roche Diagnostics Inc]). In addition, the cortisol levels at 12:00, 18:00, and 23:00 h were 4.4, 3.4, and 3.4 µg/dL, respectively. Although adrenal insufficiency could be caused by prior exogenous corticosteroid use, load test with adrenocorticotropic hormone (ACTH: tetracosactide acetate 250 μg) was performed and the ACTH-stimulated cortisol response was low (cortisol less than 18 μg/dL as a basis for adrenal insufficiency). Load test with corticotropin-releasing hormone (CRH:corticorelin 100 μg) was also performed and the CRH-stimulated ACTH response was intact, but the cortisol response was low. These results indicated secondary adrenocortical hypofunction, probably due to the ointment containing glucocorticoid.
In addition to a plain CT, contrast-enhanced CT was also performed (Fig. 1B). The bilateral tumor showed a clear margin. Cystic regions were clearly detected in the right adrenal region. Magnetic resonance imaging (MRI) revealed some encapsulated fluid lesions in the right-sided mass with high signal intensity on T2-weighted images (Fig. 1C and 1D), suggesting the possibility of cysts or hemangiomas. The left-sided mass showed higher signal intensity than the liver on T2-weighted images. On chemical shift MRI (Fig. 1E and 1F) of the adrenal glands, the loss of signal intensity was not detected in out-of-phase imaging when compared with that of the spleen, suggesting the possibility of malignancy rather than adenoma [10]. However, on 18F-fluorodeoxyglucose positron emission tomography (PET), no suspicious malignant lesion was detected.
The patient underwent laparoscopic right adrenalectomy because the possibility of malignancy could not be excluded. The resected right adrenal gland weighed 45 g, and the tumor measured 45 × 40 × 32 mm. Representative histological findings are illustrated in Fig. 2A and 2B. The tumor was composed of compact cells with eosinophilic cytoplasm and scattered foci of clear cells. Based on the Weiss criteria, the tumor was diagnosed as an adrenocortical adenoma, and the cysts were detected adjacent to the tumor. Most of the right adrenal glands remained intact.
Figure 2. Photomicrograph of the resected tumors and adrenal glands (hematoxylin-eosin stain). A, Intact adrenal tissue (blue arrows) and tumor with a cyst in the right side. B, Enlarged view of the dotted region A. C, intact adrenal tissue (blue arrows) and tumor in the left side. D, Enlarged view of the dotted region C.
While the characteristics of the left adrenal lesion could not be determined, the left adrenal gland had a different shape from the right adrenal mass, and the possibility of malignancy could not be completely excluded. Therefore, the patient subsequently underwent laparoscopic left adrenalectomy. The resected left adrenal gland weighed 54 g, and the tumor measured 65 × 50 × 30 mm. Representative histological findings are illustrated in Fig. 2C and 2D. The histological features of the tumor in the left adrenal gland were similar to those in the right adrenal gland. The tumor on the left side was also diagnosed as an adrenocortical adenoma. No cysts were discernible in the left resected specimen, and most of the left adrenal glands remained intact.
In addition to the hematoxylin-eosin stain, we immunolocalized steroidogenic enzymes in both the resected adrenal glands (Figs. 3-5). In both tumors, immunoreactivity of 3β-hydroxysteroid dehydrogenase (HSD3β), 17α-hydroxylase, and 11β-hydroxylase (Fig. 3A and 3D) was diffusely detected but that of CYP11β2 [9, 11] was not (Fig. 3B and 3E). These results demonstrate that the tumor cells could produce cortisol but not aldosterone. Immunoreactivity of dehydroepiandrosterone-sulfotransferase (DHEA-ST) in the zona reticularis of the attached nonneoplastic adrenal cortex, which reflects the long-term dynamics of the hypothalamus-pituitary-adrenal (HPA) axis, was within normal limits (Fig. 3C and 3F). Therefore, cortisol produced by these tumors did not affect the HPA axis in the patient. Ki-67 labeling indices were 2.5% in the right adrenal tumor and less than 1% in the left adrenal tumor. The right-sided cysts were diagnosed as endothelial cysts because the monolayer lining cells were positive for CD31 immunoreactivity (Fig. 4). The nonneoplastic adrenal glands adjacent to the tumors on both sides had similar pathological features: morphologically hyperplastic in the zona glomerulosa (immunohistochemically positive for HSD3β and CYP11β2 [Fig. 3B and 3E and Fig. 5]) [9]. The final diagnosis of the resected adrenal glands following detailed analyses of steroidogenesis was that of a bilateral nonfunctional adrenocortical adenoma with cortisol-producing ability, with endothelial cyst formation and bilateral diffuse hyperplasia of the zona glomerulosa in the adjacent nonneoplastic adrenal glands.
Figure 3. Photomicrograph of the resected tumors and adrenal glands in A to C, the right side and D to F, the left side. A and D, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). The zona fasciculata and zona reticularis of the adrenal glands were positive for CYP11β1. Tumors were also positive for CYP11β1. B and E, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). Lined positivity for CYP11β2 of the zona glomerulosa was detected (blue arrows). Tumors were negative for CYP11β2. C and F, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST). The zona reticularis of the adrenal glands was positive for DHEA-ST. Tumors were negative for DHEA-ST.
Figure 4. Photomicrograph of the right-sided cystic region (immunohistochemical labeling for CD31). The monolayer lining cells of the cyst wall were CD31 positive, indicating endothelial cysts.
Figure 5. Photomicrograph of the resected intact adrenal tissue. Morphologically hyperplastic feature was detected in the zona glomerulosa. A, Hematoxylin-eosin staining. B, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). C, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). D, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST).
The postoperative course of the patient was uneventful. Hydrocortisone replacement was continued. Fludrocortisone was not administered according to a clinical practice guideline on primary adrenal insufficiency by the Japan Endocrine Society [12]. However, the clinical practice guideline of the Endocrine Society recommends mineral corticoid replacement with fludrocortisone and no restriction on salt intake [13]. Her blood pressure was 102 to 120/56 to 80 mm Hg. The patient’s blood biochemistry data were almost within the normal range. Fasting blood glucose and hemoglobin A1c levels were improved, reaching 100 mg/dL and 6.5%, respectively, without the administration of SGLT2 inhibitor or other diabetic medications (empagliflozin was stopped before the first surgery). This remission of diabetes might be caused by the reduction of body weight and cessation of the exogenous glucocorticoid.
2. Discussion
In our case, the adrenal glands showed relatively large bilateral adrenal incidentalomas (measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side) and unilateral cysts on the right side. In addition, these tumor masses showed a density of 30 to 50 H on the right side and 10 to 40 H on the left side on CT. To date, 24% of adrenal incidentalomas measuring more than 4 cm in diameter have been reported as being malignant lesions, with 90% of adrenal carcinomas having been reported to be larger than 4 cm in diameter [14]. The lipid content of the adrenal mass results in low attenuation on CT, which enables the distinction of adenomas from nonadenomas; adenomas have low attenuation (≤ 10 H) on CT [14]. Moreover, discerning the malignancy of the adrenal cystic lesions precisely, without histological diagnosis, is difficult [15]. Furthermore, the prevalence of benign adrenal cortical adenomas has been reported to increase with age [14]. In our case, surgical excision was based on the following conditions: surgical removal should be considered for nonfunctional adrenal masses measuring more than 4 cm unless there is a clear benign cause [16, 17] and should also be considered for masses measuring more than 4.6 cm or more than 20 H on CT [18]. In addition, because adrenal carcinomas could be associated with benign-appearing cysts, whole-specimen exploration of resected tissues is definitively recommended to rule out malignancy [19].
We performed multiple scans: CT, MRI, and PET. When an adrenal tumor has a large size and high attenuation as detected by CT scan, surgery without multiple scans was an appropriate option. If this case showed single laterality, we would proceed to surgery without multiple scans. However, this case manifested as a bilateral adrenal tumor. We tried to investigate the possibility of leaving the adrenal gland on the one side and begin with surgical resection of the other, but eventually surgery on both sides was needed. This is the reason for undertaking multiple scans and the separate adrenalectomies.
Approximately 15% of adrenal incidentalomas have been reported to be bilateral [14, 16]. In bilateral cases, adrenocortical hypofunction could occur owing to the damage of normal adrenal glands by tumor masses; therefore, screening of the adrenal glands’ function has been recommended [14, 16]. Adrenocortical hypofunction was observed in our case during the preoperative diagnosis. Based on low serum cortisol levels and the results of the ACTH and CRH load test, secondary but not primary adrenal insufficiency was suspected as being the cause of adrenocortical hypofunction. In fact, the postoperative histological study revealed almost intact adrenal glands and bilateral adenomas, with cortisol-producing potential, which did not influence the HPA axis because of normal histological features of the zona fasciculata and reticularis and intact expression of DHEA-ST in the zona reticularis. Therefore, the adrenal insufficiency in this case might have been caused by the temporary use of an exogeneous glucocorticoid and not by direct damage to the adrenal glands by bilateral tumors.
Adrenal endothelial cysts are rare diseases, and cases complicated with adrenal neoplasms are known to be extremely rare [6, 8], with a female predominance and a right-sided prevalence [7], as observed in our case. The pathogenesis of an endothelial cyst with an adrenocortical adenoma has been speculated by a previous study: local circulatory failure by repeated cycles of thrombus formation and recanalization and blood flow communication to a preexisting hemangioma [6].
In our case, in addition to bilateral adrenocortical adenoma with endothelial cysts, morphologically and immunohistochemically confirmed diffuse adrenal hyperplasia of the zona glomerulosa was detected. Although serum aldosterone levels, serum renin activity, and blood pressure were all within the normal range, detailed examination of the resected adrenal gland revealed diffuse hyperplasia of the zona glomerulosa, which was diffusely positive for CYP11β2. High sodium intake in the modern lifestyle has been reported to diminish the area of zona glomerulosa with aging [20, 21] as the renin-angiotensin-aldosterone system (RAAS) is relatively suppressed [20]. Consequently, elderly people usually have a smaller area of zona glomerulosa. Hyperplasia of the zona glomerulosa was detected during excessive activation of the RAAS, which further results in secondary aldosteronism [20]. The patient in our study did not have diseases causing secondary aldosteronism, but one possibility for the activated RAAS was the use of empagliflozin, an SGLT2 inhibitor, which led to diffuse hyperplasia of the zona glomerulosa. Serum renin and aldosterone levels have been reported to increase significantly with SGLT2 inhibitor use within 1 month, which is associated with a decrease in extracellular fluid [22, 23]. Inconsistent results have been reported for the changes in RAAS in long-term treatments with SGLT2 inhibitors [24]. Although renin activity and aldosterone levels both were reported to normalize after 6 months of SGLT2 inhibitor treatment in some studies [22], increased RAAS activation after 24 weeks of SGLT2 inhibitor treatment was reported in another study [25]. Dehydration is one of the most frequent adverse events of SGLT2 inhibitor use [26, 27] due to the excretion of abundant urinary glucose. In our case, although serum renin and aldosterone levels were within the normal range, urine aldosterone level was above normal, and serum aldosterone level was close to the upper limit of the normal range. In addition, our patient had increased blood hemoglobin and hematocrit levels (15.0-15.7g/dL and 43.5%-46.4%, respectively), which suggest dehydration associated with SGLT2 inhibitor treatment before the operation, which returned to normal levels (13.9-14.5g/dL and 40.5%-42.6%, respectively) after discontinuation of the SGLT2 inhibitor post operation. In our study, surgical resection of the bilateral adrenal glands for the treatment of an adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine the morphology and histology of adrenal glands under SGLT2 inhibitor treatment, leading to unexpected findings of diffuse bilateral hyperplasia of the zona glomerulosa, with no functional changes in renin and aldosterone levels, and no increase in blood pressure. These results suggest the possibility of SGLT2 inhibitors having some effect on the zona glomerulosa of the adrenal gland; for instance, the latent loss of plasma volume caused by the SGLT2 inhibitor stimulating the zona glomerulosa chronically, leading to hyperplasia.
3. Conclusion
To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts coexisted, demonstrating the complexity and difficulty of preoperative diagnosis of bilateral adrenal incidentaloma. The adrenal mass in our case was not malignant, but a large tumor with cysts should be considered for resection because potential malignancy is ruled out by detailed histopathological evaluation of the lesions. In addition, surgical resection of bilateral adrenal glands for the treatment of adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine in detail the morphology and histology of the adrenal glands under SGLT2 inhibitor treatment, leading to an unexpected finding of diffuse bilateral hyperplasia of the zona glomerulosa in nonneoplastic adrenal glands, without clinically demonstrating primary aldosteronism. Therefore, we advocate a new hypothesis that SGLT2 inhibitors affect the zona glomerulosa of the adrenal gland; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of zona glomerulosa based on the data in this singular case. Because this can be confirmed only under limited conditions, additional case reports or animal model studies on adrenal gland histology under SGLT2 inhibition are warranted.
Acknowledgments
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Abbreviations
ACTH adrenocorticotropic hormone
CRH corticotropin-releasing hormone
CT computed tomography
CYP11β2 18-hydroxylase
DHEA-ST dehydroepiandrosterone-sulfotransferase
HPA hypothalamus-pituitary-adrenal
HSD3β 3β-hydroxysteroid dehydrogenase
H Hounsfield unit
MRI magnetic resonance imaging
PET positron emission tomography
RAAS renin-angiotensin-aldosterone system
SGLT2 sodium-glucose co-transport protein-2
Additional Information
Disclosure Summary: The authors have no conflicts of interest to report.
Data Availability
Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study. | EMPAGLIFLOZIN | DrugsGivenReaction | CC BY-NC-ND | 33381672 | 19,439,388 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adrenal neoplasm'. | A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.
Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.
Adrenal cysts are rare cystic masses that are detected incidentally during autopsy in 0.06% of the population [1]. Approximately 6% of tumors detected as adrenal incidentalomas are adrenal cysts, as observed from the data of surgical series [2, 3]; however, a recent prospective study clarified that the incidence is much lower (< 1%) [4]. Adrenal cysts are classified as vascular or endothelial, epithelial, or parasitic [1, 5]. Pseudocysts are the most common type of adrenal cysts [6, 7]. Endothelial cysts associated with adrenal neoplasms are rare, with only a few reported cases [6, 8]. In addition, the cases of unilateral endothelial cysts and bilateral adrenal neoplasms have not been reported, to the best of our knowledge.
Primary aldosteronism is caused by the autonomous secretion of aldosterone owing to aldosterone-producing adenoma, multiple adrenocortical micronodules, and diffuse adrenocortical hyperplasia of the zona glomerulosa [9]. These conditions are known to be associated with high serum aldosterone and low renin levels, resulting in hypertension. However, we recently experienced a case of diffuse hyperplasia of the zona glomerulosa, positive for 18-hydroxylase: aldosterone synthase (CYP11β2), in which the patient had normal serum aldosterone levels, renin activity, and blood pressure.
Here, we report a rare case of bilateral adrenal adenomas with unilateral adrenal endothelial cysts. The possibility of sodium-glucose cotransporter protein 2 (SGLT2) inhibitor causing bilateral hyperplasia of the zona glomerulosa of the adrenal gland will also be discussed.
1. Case Presentation
A 65-year-old Japanese woman was referred to our hospital for characterization of the bilateral adrenal incidentaloma. At age 63, the patient was diagnosed with type 2 diabetes, which had been treated with diet and exercise therapy, and a gallstone identified by abdominal ultrasonography at a nearby clinic. Other than the diabetes and gallstone, she did not have any past medical history that needs specific mention. At age 64, the patient was administered an SGLT2 inhibitor, empagliflozin (10 mg/day), without any other medications and underwent abdominal ultrasonography for follow-up of the gallstone; however, adrenal masses were not identified at this point. At age 65, adrenal masses were incidentally identified during the abdominal ultrasonography during the follow-up examination of the gallstone. Consequently, subsequent plain abdominal computed tomography (CT) was performed, which revealed bilateral masses measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side (Fig. 1A). The right-sided mass was flat, with a small high-density spot, and heterogeneous, with a high-density (30-50 Hounsfield units [H]) and a low-density area (10-20 H). The left-sided mass was almost round with a relatively heterogeneous density (10-40 H).
Figure 1. Computed tomography (CT) scans of the right and left adrenal area. A, Plain CT showing a mass on the left and right sides (measuring 6.2 × 2.5 cm and 4.6 × 4.1 cm, respectively). B, Contrast-enhanced CT. C to F, Magnetic resonance imaging (MRI). C and D, T2-weighted images and images E, in phase and F, out of phase using chemical shift MRI.
The patient was admitted to our hospital for detailed examination. On admission, the patient did not present any signs or symptoms associated with excess adrenal cortical hormone levels or its deficiency. She had been taking an antidiabetic drug (empagliflozin, 10 mg/day) for approximately 1 year, and her diabetes was well controlled (fasting blood glucose: 116 mg/dL, glycated hemoglobin [hemoglobin A1c]: 6.9%). Between the third and first month prior to her introduction to our hospital, the patient used an ointment containing betamethasone butyrate propionate (exogenous glucocorticoid) for dermatitis. Physical examination revealed no significant findings. Clinical parameters were as follows: body height, 145.9 cm; body weight, 55.9 kg; blood pressure, 122/60 mm Hg; and heart rate, 60 beats/min. The laboratory data are presented in Table 1. The complete blood count and blood biochemistry tests were almost within the normal range.
Table 1. Laboratory findings of the patient
Peripheral blood Endocrinological data Load test
WBC 6060/mm3 (3300-8600) (Plasma) (CRH load)
RBC 462 × 104/mm3 (386-492) Epinephrine 24 pg/mL (0-100) ACTH 0 min 23.1 pg/mL
Hb 15.0 g/dL (11.6-14.8) Norepinephrine 304 pg/mL (100-450) 30 min 185.9 pg/mL
Ht 44.3% (35.1-44.4) Dopamine 10 pg/mL (0-20) 60 min 155.2 pg/mL
Plt 17.8 × 104/mm3 (15.8-34.8) Renin 2.3 ng/mL/h (0.3-5.4) 90 min 65.6 pg/mL
Aldosterone 149 pg/mL (29.9-159) 120 min 37.3 pg/mL
Biochemical data ARR 65 (< 200) Cortisol 0 min 4.5 μg/dL
T.P. 7.2 g/dL (6.6-8.1) ACTH (06:00) 32.0 pg/mL (7.2-63.3) 30 min 4.8 μg/dL
Albumin 4.2 g/dL (4.1-5.1) (12:00) 10.4 pg/mL 60 min 5.5 μg/dL
T.Bil 0.6 mg/dL (0.4-1.5) (18:00) 12.5 pg/mL 90 min 5.7 μg/dL
AST 25 U/L (13-30) (23:00) 13.6 pg/mL 120 min 5.5 μg/dL
ALT 29 U/L (7-23) Cortisol (06:00) 7.0 μg/dL (6.2-19.4)
LDH 248 U/L (124-222) (12:00) 4.4 μg/dL (ACTH load)
ALP 156 U/L (106-322) (18:00) 3.4 μg/dL Cortisol 0 min 4.3 μg/dL
rGTP 28 U/L (9-32) (23:00) 3.4 μg/dL 30 min 4.5 μg/dL
BUN 13 mg/dL (8-20) DHEA-S 96 μg/dL (12-133) 60 min 5.2 μg/dL
Crea 0.68 mg/dL (0.46-0.79) 90 min 5.7 μg/dL
Na 138 mEq/L (138-145) (Urine) 120 min 6.0 μg/dL
K 4.2 mEq/L (3.6-4.8) Epinephrine 8.2 μg/d (3.4-26.9)
Cl 105 mEq/L (101-108) Norepinephrine 133.3 μg/d (48.6-168.4)
Glucose 116 mg/dL (73-109) Dopamine 800.2 μg/d (365-961.5)
T.chol 177 mg/dL (142-220) Aldosterone 11 μg/d (0-10)
HbA1c 6.9% (4.9-6.2) Cortisol 75.3 μg/d (11.2-80.3)
sIL-2R 325 U/mL (121-613)
Reference ranges are in parentheses.
Abbreviations: ACTH, adrenocorticotropin; ALP, alkaline phosphatase; ALT, alanine transferase; ARR, aldosterone/renin ratio; AST, aspartate transaminase; BUN, blood urea nitrogen; Cl, chlorine; Crea, creatinine; DHEA-S, dehydroepiandrosterone-sulfate; Hb, hemoglobin; HbA1c, glycated hemoglobin; Ht, hematocrit; K, potassium; LDH, lactate dehydrogenase; Na, natrium; Plt, platelets; RBC, red blood cells; rGTP, γ-glutamyl transferase; sIL-2R, soluble interleukin-2 receptor; T.Bil, total bilirubin; T.chol, total cholesterol; T.P, total protein; WBC, white blood cells.
Endocrinological data are also presented in Table 1. Blood and 24-hour urine catecholamines were within the normal range. Plasma aldosterone concentration of 149 pg/mL, plasma renin activity of 2.3 ng/mL/h, and aldosterone/renin ratio of 65 were within the normal range. Urine aldosterone level (11 µg/day) was slightly elevated. Cortisol and adrenocorticotropin (ACTH) levels early in the morning were 5.3 µg/dL and 15.8 pg/mL (at an outpatient clinic) and 7.0 µg/dL and 32.0 pg/mL (after hospitalization), respectively (cortisol and ACTH levels were measured by Eclusys Cortisol II and Eclusys ACTH; reference values were 6.2-19.4 µg/dL and 7.2-63.3 pg/mL, respectively [Roche Diagnostics Inc]). In addition, the cortisol levels at 12:00, 18:00, and 23:00 h were 4.4, 3.4, and 3.4 µg/dL, respectively. Although adrenal insufficiency could be caused by prior exogenous corticosteroid use, load test with adrenocorticotropic hormone (ACTH: tetracosactide acetate 250 μg) was performed and the ACTH-stimulated cortisol response was low (cortisol less than 18 μg/dL as a basis for adrenal insufficiency). Load test with corticotropin-releasing hormone (CRH:corticorelin 100 μg) was also performed and the CRH-stimulated ACTH response was intact, but the cortisol response was low. These results indicated secondary adrenocortical hypofunction, probably due to the ointment containing glucocorticoid.
In addition to a plain CT, contrast-enhanced CT was also performed (Fig. 1B). The bilateral tumor showed a clear margin. Cystic regions were clearly detected in the right adrenal region. Magnetic resonance imaging (MRI) revealed some encapsulated fluid lesions in the right-sided mass with high signal intensity on T2-weighted images (Fig. 1C and 1D), suggesting the possibility of cysts or hemangiomas. The left-sided mass showed higher signal intensity than the liver on T2-weighted images. On chemical shift MRI (Fig. 1E and 1F) of the adrenal glands, the loss of signal intensity was not detected in out-of-phase imaging when compared with that of the spleen, suggesting the possibility of malignancy rather than adenoma [10]. However, on 18F-fluorodeoxyglucose positron emission tomography (PET), no suspicious malignant lesion was detected.
The patient underwent laparoscopic right adrenalectomy because the possibility of malignancy could not be excluded. The resected right adrenal gland weighed 45 g, and the tumor measured 45 × 40 × 32 mm. Representative histological findings are illustrated in Fig. 2A and 2B. The tumor was composed of compact cells with eosinophilic cytoplasm and scattered foci of clear cells. Based on the Weiss criteria, the tumor was diagnosed as an adrenocortical adenoma, and the cysts were detected adjacent to the tumor. Most of the right adrenal glands remained intact.
Figure 2. Photomicrograph of the resected tumors and adrenal glands (hematoxylin-eosin stain). A, Intact adrenal tissue (blue arrows) and tumor with a cyst in the right side. B, Enlarged view of the dotted region A. C, intact adrenal tissue (blue arrows) and tumor in the left side. D, Enlarged view of the dotted region C.
While the characteristics of the left adrenal lesion could not be determined, the left adrenal gland had a different shape from the right adrenal mass, and the possibility of malignancy could not be completely excluded. Therefore, the patient subsequently underwent laparoscopic left adrenalectomy. The resected left adrenal gland weighed 54 g, and the tumor measured 65 × 50 × 30 mm. Representative histological findings are illustrated in Fig. 2C and 2D. The histological features of the tumor in the left adrenal gland were similar to those in the right adrenal gland. The tumor on the left side was also diagnosed as an adrenocortical adenoma. No cysts were discernible in the left resected specimen, and most of the left adrenal glands remained intact.
In addition to the hematoxylin-eosin stain, we immunolocalized steroidogenic enzymes in both the resected adrenal glands (Figs. 3-5). In both tumors, immunoreactivity of 3β-hydroxysteroid dehydrogenase (HSD3β), 17α-hydroxylase, and 11β-hydroxylase (Fig. 3A and 3D) was diffusely detected but that of CYP11β2 [9, 11] was not (Fig. 3B and 3E). These results demonstrate that the tumor cells could produce cortisol but not aldosterone. Immunoreactivity of dehydroepiandrosterone-sulfotransferase (DHEA-ST) in the zona reticularis of the attached nonneoplastic adrenal cortex, which reflects the long-term dynamics of the hypothalamus-pituitary-adrenal (HPA) axis, was within normal limits (Fig. 3C and 3F). Therefore, cortisol produced by these tumors did not affect the HPA axis in the patient. Ki-67 labeling indices were 2.5% in the right adrenal tumor and less than 1% in the left adrenal tumor. The right-sided cysts were diagnosed as endothelial cysts because the monolayer lining cells were positive for CD31 immunoreactivity (Fig. 4). The nonneoplastic adrenal glands adjacent to the tumors on both sides had similar pathological features: morphologically hyperplastic in the zona glomerulosa (immunohistochemically positive for HSD3β and CYP11β2 [Fig. 3B and 3E and Fig. 5]) [9]. The final diagnosis of the resected adrenal glands following detailed analyses of steroidogenesis was that of a bilateral nonfunctional adrenocortical adenoma with cortisol-producing ability, with endothelial cyst formation and bilateral diffuse hyperplasia of the zona glomerulosa in the adjacent nonneoplastic adrenal glands.
Figure 3. Photomicrograph of the resected tumors and adrenal glands in A to C, the right side and D to F, the left side. A and D, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). The zona fasciculata and zona reticularis of the adrenal glands were positive for CYP11β1. Tumors were also positive for CYP11β1. B and E, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). Lined positivity for CYP11β2 of the zona glomerulosa was detected (blue arrows). Tumors were negative for CYP11β2. C and F, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST). The zona reticularis of the adrenal glands was positive for DHEA-ST. Tumors were negative for DHEA-ST.
Figure 4. Photomicrograph of the right-sided cystic region (immunohistochemical labeling for CD31). The monolayer lining cells of the cyst wall were CD31 positive, indicating endothelial cysts.
Figure 5. Photomicrograph of the resected intact adrenal tissue. Morphologically hyperplastic feature was detected in the zona glomerulosa. A, Hematoxylin-eosin staining. B, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). C, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). D, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST).
The postoperative course of the patient was uneventful. Hydrocortisone replacement was continued. Fludrocortisone was not administered according to a clinical practice guideline on primary adrenal insufficiency by the Japan Endocrine Society [12]. However, the clinical practice guideline of the Endocrine Society recommends mineral corticoid replacement with fludrocortisone and no restriction on salt intake [13]. Her blood pressure was 102 to 120/56 to 80 mm Hg. The patient’s blood biochemistry data were almost within the normal range. Fasting blood glucose and hemoglobin A1c levels were improved, reaching 100 mg/dL and 6.5%, respectively, without the administration of SGLT2 inhibitor or other diabetic medications (empagliflozin was stopped before the first surgery). This remission of diabetes might be caused by the reduction of body weight and cessation of the exogenous glucocorticoid.
2. Discussion
In our case, the adrenal glands showed relatively large bilateral adrenal incidentalomas (measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side) and unilateral cysts on the right side. In addition, these tumor masses showed a density of 30 to 50 H on the right side and 10 to 40 H on the left side on CT. To date, 24% of adrenal incidentalomas measuring more than 4 cm in diameter have been reported as being malignant lesions, with 90% of adrenal carcinomas having been reported to be larger than 4 cm in diameter [14]. The lipid content of the adrenal mass results in low attenuation on CT, which enables the distinction of adenomas from nonadenomas; adenomas have low attenuation (≤ 10 H) on CT [14]. Moreover, discerning the malignancy of the adrenal cystic lesions precisely, without histological diagnosis, is difficult [15]. Furthermore, the prevalence of benign adrenal cortical adenomas has been reported to increase with age [14]. In our case, surgical excision was based on the following conditions: surgical removal should be considered for nonfunctional adrenal masses measuring more than 4 cm unless there is a clear benign cause [16, 17] and should also be considered for masses measuring more than 4.6 cm or more than 20 H on CT [18]. In addition, because adrenal carcinomas could be associated with benign-appearing cysts, whole-specimen exploration of resected tissues is definitively recommended to rule out malignancy [19].
We performed multiple scans: CT, MRI, and PET. When an adrenal tumor has a large size and high attenuation as detected by CT scan, surgery without multiple scans was an appropriate option. If this case showed single laterality, we would proceed to surgery without multiple scans. However, this case manifested as a bilateral adrenal tumor. We tried to investigate the possibility of leaving the adrenal gland on the one side and begin with surgical resection of the other, but eventually surgery on both sides was needed. This is the reason for undertaking multiple scans and the separate adrenalectomies.
Approximately 15% of adrenal incidentalomas have been reported to be bilateral [14, 16]. In bilateral cases, adrenocortical hypofunction could occur owing to the damage of normal adrenal glands by tumor masses; therefore, screening of the adrenal glands’ function has been recommended [14, 16]. Adrenocortical hypofunction was observed in our case during the preoperative diagnosis. Based on low serum cortisol levels and the results of the ACTH and CRH load test, secondary but not primary adrenal insufficiency was suspected as being the cause of adrenocortical hypofunction. In fact, the postoperative histological study revealed almost intact adrenal glands and bilateral adenomas, with cortisol-producing potential, which did not influence the HPA axis because of normal histological features of the zona fasciculata and reticularis and intact expression of DHEA-ST in the zona reticularis. Therefore, the adrenal insufficiency in this case might have been caused by the temporary use of an exogeneous glucocorticoid and not by direct damage to the adrenal glands by bilateral tumors.
Adrenal endothelial cysts are rare diseases, and cases complicated with adrenal neoplasms are known to be extremely rare [6, 8], with a female predominance and a right-sided prevalence [7], as observed in our case. The pathogenesis of an endothelial cyst with an adrenocortical adenoma has been speculated by a previous study: local circulatory failure by repeated cycles of thrombus formation and recanalization and blood flow communication to a preexisting hemangioma [6].
In our case, in addition to bilateral adrenocortical adenoma with endothelial cysts, morphologically and immunohistochemically confirmed diffuse adrenal hyperplasia of the zona glomerulosa was detected. Although serum aldosterone levels, serum renin activity, and blood pressure were all within the normal range, detailed examination of the resected adrenal gland revealed diffuse hyperplasia of the zona glomerulosa, which was diffusely positive for CYP11β2. High sodium intake in the modern lifestyle has been reported to diminish the area of zona glomerulosa with aging [20, 21] as the renin-angiotensin-aldosterone system (RAAS) is relatively suppressed [20]. Consequently, elderly people usually have a smaller area of zona glomerulosa. Hyperplasia of the zona glomerulosa was detected during excessive activation of the RAAS, which further results in secondary aldosteronism [20]. The patient in our study did not have diseases causing secondary aldosteronism, but one possibility for the activated RAAS was the use of empagliflozin, an SGLT2 inhibitor, which led to diffuse hyperplasia of the zona glomerulosa. Serum renin and aldosterone levels have been reported to increase significantly with SGLT2 inhibitor use within 1 month, which is associated with a decrease in extracellular fluid [22, 23]. Inconsistent results have been reported for the changes in RAAS in long-term treatments with SGLT2 inhibitors [24]. Although renin activity and aldosterone levels both were reported to normalize after 6 months of SGLT2 inhibitor treatment in some studies [22], increased RAAS activation after 24 weeks of SGLT2 inhibitor treatment was reported in another study [25]. Dehydration is one of the most frequent adverse events of SGLT2 inhibitor use [26, 27] due to the excretion of abundant urinary glucose. In our case, although serum renin and aldosterone levels were within the normal range, urine aldosterone level was above normal, and serum aldosterone level was close to the upper limit of the normal range. In addition, our patient had increased blood hemoglobin and hematocrit levels (15.0-15.7g/dL and 43.5%-46.4%, respectively), which suggest dehydration associated with SGLT2 inhibitor treatment before the operation, which returned to normal levels (13.9-14.5g/dL and 40.5%-42.6%, respectively) after discontinuation of the SGLT2 inhibitor post operation. In our study, surgical resection of the bilateral adrenal glands for the treatment of an adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine the morphology and histology of adrenal glands under SGLT2 inhibitor treatment, leading to unexpected findings of diffuse bilateral hyperplasia of the zona glomerulosa, with no functional changes in renin and aldosterone levels, and no increase in blood pressure. These results suggest the possibility of SGLT2 inhibitors having some effect on the zona glomerulosa of the adrenal gland; for instance, the latent loss of plasma volume caused by the SGLT2 inhibitor stimulating the zona glomerulosa chronically, leading to hyperplasia.
3. Conclusion
To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts coexisted, demonstrating the complexity and difficulty of preoperative diagnosis of bilateral adrenal incidentaloma. The adrenal mass in our case was not malignant, but a large tumor with cysts should be considered for resection because potential malignancy is ruled out by detailed histopathological evaluation of the lesions. In addition, surgical resection of bilateral adrenal glands for the treatment of adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine in detail the morphology and histology of the adrenal glands under SGLT2 inhibitor treatment, leading to an unexpected finding of diffuse bilateral hyperplasia of the zona glomerulosa in nonneoplastic adrenal glands, without clinically demonstrating primary aldosteronism. Therefore, we advocate a new hypothesis that SGLT2 inhibitors affect the zona glomerulosa of the adrenal gland; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of zona glomerulosa based on the data in this singular case. Because this can be confirmed only under limited conditions, additional case reports or animal model studies on adrenal gland histology under SGLT2 inhibition are warranted.
Acknowledgments
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Abbreviations
ACTH adrenocorticotropic hormone
CRH corticotropin-releasing hormone
CT computed tomography
CYP11β2 18-hydroxylase
DHEA-ST dehydroepiandrosterone-sulfotransferase
HPA hypothalamus-pituitary-adrenal
HSD3β 3β-hydroxysteroid dehydrogenase
H Hounsfield unit
MRI magnetic resonance imaging
PET positron emission tomography
RAAS renin-angiotensin-aldosterone system
SGLT2 sodium-glucose co-transport protein-2
Additional Information
Disclosure Summary: The authors have no conflicts of interest to report.
Data Availability
Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study. | EMPAGLIFLOZIN | DrugsGivenReaction | CC BY-NC-ND | 33381672 | 19,439,388 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperplasia adrenal'. | A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.
Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.
Adrenal cysts are rare cystic masses that are detected incidentally during autopsy in 0.06% of the population [1]. Approximately 6% of tumors detected as adrenal incidentalomas are adrenal cysts, as observed from the data of surgical series [2, 3]; however, a recent prospective study clarified that the incidence is much lower (< 1%) [4]. Adrenal cysts are classified as vascular or endothelial, epithelial, or parasitic [1, 5]. Pseudocysts are the most common type of adrenal cysts [6, 7]. Endothelial cysts associated with adrenal neoplasms are rare, with only a few reported cases [6, 8]. In addition, the cases of unilateral endothelial cysts and bilateral adrenal neoplasms have not been reported, to the best of our knowledge.
Primary aldosteronism is caused by the autonomous secretion of aldosterone owing to aldosterone-producing adenoma, multiple adrenocortical micronodules, and diffuse adrenocortical hyperplasia of the zona glomerulosa [9]. These conditions are known to be associated with high serum aldosterone and low renin levels, resulting in hypertension. However, we recently experienced a case of diffuse hyperplasia of the zona glomerulosa, positive for 18-hydroxylase: aldosterone synthase (CYP11β2), in which the patient had normal serum aldosterone levels, renin activity, and blood pressure.
Here, we report a rare case of bilateral adrenal adenomas with unilateral adrenal endothelial cysts. The possibility of sodium-glucose cotransporter protein 2 (SGLT2) inhibitor causing bilateral hyperplasia of the zona glomerulosa of the adrenal gland will also be discussed.
1. Case Presentation
A 65-year-old Japanese woman was referred to our hospital for characterization of the bilateral adrenal incidentaloma. At age 63, the patient was diagnosed with type 2 diabetes, which had been treated with diet and exercise therapy, and a gallstone identified by abdominal ultrasonography at a nearby clinic. Other than the diabetes and gallstone, she did not have any past medical history that needs specific mention. At age 64, the patient was administered an SGLT2 inhibitor, empagliflozin (10 mg/day), without any other medications and underwent abdominal ultrasonography for follow-up of the gallstone; however, adrenal masses were not identified at this point. At age 65, adrenal masses were incidentally identified during the abdominal ultrasonography during the follow-up examination of the gallstone. Consequently, subsequent plain abdominal computed tomography (CT) was performed, which revealed bilateral masses measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side (Fig. 1A). The right-sided mass was flat, with a small high-density spot, and heterogeneous, with a high-density (30-50 Hounsfield units [H]) and a low-density area (10-20 H). The left-sided mass was almost round with a relatively heterogeneous density (10-40 H).
Figure 1. Computed tomography (CT) scans of the right and left adrenal area. A, Plain CT showing a mass on the left and right sides (measuring 6.2 × 2.5 cm and 4.6 × 4.1 cm, respectively). B, Contrast-enhanced CT. C to F, Magnetic resonance imaging (MRI). C and D, T2-weighted images and images E, in phase and F, out of phase using chemical shift MRI.
The patient was admitted to our hospital for detailed examination. On admission, the patient did not present any signs or symptoms associated with excess adrenal cortical hormone levels or its deficiency. She had been taking an antidiabetic drug (empagliflozin, 10 mg/day) for approximately 1 year, and her diabetes was well controlled (fasting blood glucose: 116 mg/dL, glycated hemoglobin [hemoglobin A1c]: 6.9%). Between the third and first month prior to her introduction to our hospital, the patient used an ointment containing betamethasone butyrate propionate (exogenous glucocorticoid) for dermatitis. Physical examination revealed no significant findings. Clinical parameters were as follows: body height, 145.9 cm; body weight, 55.9 kg; blood pressure, 122/60 mm Hg; and heart rate, 60 beats/min. The laboratory data are presented in Table 1. The complete blood count and blood biochemistry tests were almost within the normal range.
Table 1. Laboratory findings of the patient
Peripheral blood Endocrinological data Load test
WBC 6060/mm3 (3300-8600) (Plasma) (CRH load)
RBC 462 × 104/mm3 (386-492) Epinephrine 24 pg/mL (0-100) ACTH 0 min 23.1 pg/mL
Hb 15.0 g/dL (11.6-14.8) Norepinephrine 304 pg/mL (100-450) 30 min 185.9 pg/mL
Ht 44.3% (35.1-44.4) Dopamine 10 pg/mL (0-20) 60 min 155.2 pg/mL
Plt 17.8 × 104/mm3 (15.8-34.8) Renin 2.3 ng/mL/h (0.3-5.4) 90 min 65.6 pg/mL
Aldosterone 149 pg/mL (29.9-159) 120 min 37.3 pg/mL
Biochemical data ARR 65 (< 200) Cortisol 0 min 4.5 μg/dL
T.P. 7.2 g/dL (6.6-8.1) ACTH (06:00) 32.0 pg/mL (7.2-63.3) 30 min 4.8 μg/dL
Albumin 4.2 g/dL (4.1-5.1) (12:00) 10.4 pg/mL 60 min 5.5 μg/dL
T.Bil 0.6 mg/dL (0.4-1.5) (18:00) 12.5 pg/mL 90 min 5.7 μg/dL
AST 25 U/L (13-30) (23:00) 13.6 pg/mL 120 min 5.5 μg/dL
ALT 29 U/L (7-23) Cortisol (06:00) 7.0 μg/dL (6.2-19.4)
LDH 248 U/L (124-222) (12:00) 4.4 μg/dL (ACTH load)
ALP 156 U/L (106-322) (18:00) 3.4 μg/dL Cortisol 0 min 4.3 μg/dL
rGTP 28 U/L (9-32) (23:00) 3.4 μg/dL 30 min 4.5 μg/dL
BUN 13 mg/dL (8-20) DHEA-S 96 μg/dL (12-133) 60 min 5.2 μg/dL
Crea 0.68 mg/dL (0.46-0.79) 90 min 5.7 μg/dL
Na 138 mEq/L (138-145) (Urine) 120 min 6.0 μg/dL
K 4.2 mEq/L (3.6-4.8) Epinephrine 8.2 μg/d (3.4-26.9)
Cl 105 mEq/L (101-108) Norepinephrine 133.3 μg/d (48.6-168.4)
Glucose 116 mg/dL (73-109) Dopamine 800.2 μg/d (365-961.5)
T.chol 177 mg/dL (142-220) Aldosterone 11 μg/d (0-10)
HbA1c 6.9% (4.9-6.2) Cortisol 75.3 μg/d (11.2-80.3)
sIL-2R 325 U/mL (121-613)
Reference ranges are in parentheses.
Abbreviations: ACTH, adrenocorticotropin; ALP, alkaline phosphatase; ALT, alanine transferase; ARR, aldosterone/renin ratio; AST, aspartate transaminase; BUN, blood urea nitrogen; Cl, chlorine; Crea, creatinine; DHEA-S, dehydroepiandrosterone-sulfate; Hb, hemoglobin; HbA1c, glycated hemoglobin; Ht, hematocrit; K, potassium; LDH, lactate dehydrogenase; Na, natrium; Plt, platelets; RBC, red blood cells; rGTP, γ-glutamyl transferase; sIL-2R, soluble interleukin-2 receptor; T.Bil, total bilirubin; T.chol, total cholesterol; T.P, total protein; WBC, white blood cells.
Endocrinological data are also presented in Table 1. Blood and 24-hour urine catecholamines were within the normal range. Plasma aldosterone concentration of 149 pg/mL, plasma renin activity of 2.3 ng/mL/h, and aldosterone/renin ratio of 65 were within the normal range. Urine aldosterone level (11 µg/day) was slightly elevated. Cortisol and adrenocorticotropin (ACTH) levels early in the morning were 5.3 µg/dL and 15.8 pg/mL (at an outpatient clinic) and 7.0 µg/dL and 32.0 pg/mL (after hospitalization), respectively (cortisol and ACTH levels were measured by Eclusys Cortisol II and Eclusys ACTH; reference values were 6.2-19.4 µg/dL and 7.2-63.3 pg/mL, respectively [Roche Diagnostics Inc]). In addition, the cortisol levels at 12:00, 18:00, and 23:00 h were 4.4, 3.4, and 3.4 µg/dL, respectively. Although adrenal insufficiency could be caused by prior exogenous corticosteroid use, load test with adrenocorticotropic hormone (ACTH: tetracosactide acetate 250 μg) was performed and the ACTH-stimulated cortisol response was low (cortisol less than 18 μg/dL as a basis for adrenal insufficiency). Load test with corticotropin-releasing hormone (CRH:corticorelin 100 μg) was also performed and the CRH-stimulated ACTH response was intact, but the cortisol response was low. These results indicated secondary adrenocortical hypofunction, probably due to the ointment containing glucocorticoid.
In addition to a plain CT, contrast-enhanced CT was also performed (Fig. 1B). The bilateral tumor showed a clear margin. Cystic regions were clearly detected in the right adrenal region. Magnetic resonance imaging (MRI) revealed some encapsulated fluid lesions in the right-sided mass with high signal intensity on T2-weighted images (Fig. 1C and 1D), suggesting the possibility of cysts or hemangiomas. The left-sided mass showed higher signal intensity than the liver on T2-weighted images. On chemical shift MRI (Fig. 1E and 1F) of the adrenal glands, the loss of signal intensity was not detected in out-of-phase imaging when compared with that of the spleen, suggesting the possibility of malignancy rather than adenoma [10]. However, on 18F-fluorodeoxyglucose positron emission tomography (PET), no suspicious malignant lesion was detected.
The patient underwent laparoscopic right adrenalectomy because the possibility of malignancy could not be excluded. The resected right adrenal gland weighed 45 g, and the tumor measured 45 × 40 × 32 mm. Representative histological findings are illustrated in Fig. 2A and 2B. The tumor was composed of compact cells with eosinophilic cytoplasm and scattered foci of clear cells. Based on the Weiss criteria, the tumor was diagnosed as an adrenocortical adenoma, and the cysts were detected adjacent to the tumor. Most of the right adrenal glands remained intact.
Figure 2. Photomicrograph of the resected tumors and adrenal glands (hematoxylin-eosin stain). A, Intact adrenal tissue (blue arrows) and tumor with a cyst in the right side. B, Enlarged view of the dotted region A. C, intact adrenal tissue (blue arrows) and tumor in the left side. D, Enlarged view of the dotted region C.
While the characteristics of the left adrenal lesion could not be determined, the left adrenal gland had a different shape from the right adrenal mass, and the possibility of malignancy could not be completely excluded. Therefore, the patient subsequently underwent laparoscopic left adrenalectomy. The resected left adrenal gland weighed 54 g, and the tumor measured 65 × 50 × 30 mm. Representative histological findings are illustrated in Fig. 2C and 2D. The histological features of the tumor in the left adrenal gland were similar to those in the right adrenal gland. The tumor on the left side was also diagnosed as an adrenocortical adenoma. No cysts were discernible in the left resected specimen, and most of the left adrenal glands remained intact.
In addition to the hematoxylin-eosin stain, we immunolocalized steroidogenic enzymes in both the resected adrenal glands (Figs. 3-5). In both tumors, immunoreactivity of 3β-hydroxysteroid dehydrogenase (HSD3β), 17α-hydroxylase, and 11β-hydroxylase (Fig. 3A and 3D) was diffusely detected but that of CYP11β2 [9, 11] was not (Fig. 3B and 3E). These results demonstrate that the tumor cells could produce cortisol but not aldosterone. Immunoreactivity of dehydroepiandrosterone-sulfotransferase (DHEA-ST) in the zona reticularis of the attached nonneoplastic adrenal cortex, which reflects the long-term dynamics of the hypothalamus-pituitary-adrenal (HPA) axis, was within normal limits (Fig. 3C and 3F). Therefore, cortisol produced by these tumors did not affect the HPA axis in the patient. Ki-67 labeling indices were 2.5% in the right adrenal tumor and less than 1% in the left adrenal tumor. The right-sided cysts were diagnosed as endothelial cysts because the monolayer lining cells were positive for CD31 immunoreactivity (Fig. 4). The nonneoplastic adrenal glands adjacent to the tumors on both sides had similar pathological features: morphologically hyperplastic in the zona glomerulosa (immunohistochemically positive for HSD3β and CYP11β2 [Fig. 3B and 3E and Fig. 5]) [9]. The final diagnosis of the resected adrenal glands following detailed analyses of steroidogenesis was that of a bilateral nonfunctional adrenocortical adenoma with cortisol-producing ability, with endothelial cyst formation and bilateral diffuse hyperplasia of the zona glomerulosa in the adjacent nonneoplastic adrenal glands.
Figure 3. Photomicrograph of the resected tumors and adrenal glands in A to C, the right side and D to F, the left side. A and D, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). The zona fasciculata and zona reticularis of the adrenal glands were positive for CYP11β1. Tumors were also positive for CYP11β1. B and E, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). Lined positivity for CYP11β2 of the zona glomerulosa was detected (blue arrows). Tumors were negative for CYP11β2. C and F, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST). The zona reticularis of the adrenal glands was positive for DHEA-ST. Tumors were negative for DHEA-ST.
Figure 4. Photomicrograph of the right-sided cystic region (immunohistochemical labeling for CD31). The monolayer lining cells of the cyst wall were CD31 positive, indicating endothelial cysts.
Figure 5. Photomicrograph of the resected intact adrenal tissue. Morphologically hyperplastic feature was detected in the zona glomerulosa. A, Hematoxylin-eosin staining. B, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). C, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). D, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST).
The postoperative course of the patient was uneventful. Hydrocortisone replacement was continued. Fludrocortisone was not administered according to a clinical practice guideline on primary adrenal insufficiency by the Japan Endocrine Society [12]. However, the clinical practice guideline of the Endocrine Society recommends mineral corticoid replacement with fludrocortisone and no restriction on salt intake [13]. Her blood pressure was 102 to 120/56 to 80 mm Hg. The patient’s blood biochemistry data were almost within the normal range. Fasting blood glucose and hemoglobin A1c levels were improved, reaching 100 mg/dL and 6.5%, respectively, without the administration of SGLT2 inhibitor or other diabetic medications (empagliflozin was stopped before the first surgery). This remission of diabetes might be caused by the reduction of body weight and cessation of the exogenous glucocorticoid.
2. Discussion
In our case, the adrenal glands showed relatively large bilateral adrenal incidentalomas (measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side) and unilateral cysts on the right side. In addition, these tumor masses showed a density of 30 to 50 H on the right side and 10 to 40 H on the left side on CT. To date, 24% of adrenal incidentalomas measuring more than 4 cm in diameter have been reported as being malignant lesions, with 90% of adrenal carcinomas having been reported to be larger than 4 cm in diameter [14]. The lipid content of the adrenal mass results in low attenuation on CT, which enables the distinction of adenomas from nonadenomas; adenomas have low attenuation (≤ 10 H) on CT [14]. Moreover, discerning the malignancy of the adrenal cystic lesions precisely, without histological diagnosis, is difficult [15]. Furthermore, the prevalence of benign adrenal cortical adenomas has been reported to increase with age [14]. In our case, surgical excision was based on the following conditions: surgical removal should be considered for nonfunctional adrenal masses measuring more than 4 cm unless there is a clear benign cause [16, 17] and should also be considered for masses measuring more than 4.6 cm or more than 20 H on CT [18]. In addition, because adrenal carcinomas could be associated with benign-appearing cysts, whole-specimen exploration of resected tissues is definitively recommended to rule out malignancy [19].
We performed multiple scans: CT, MRI, and PET. When an adrenal tumor has a large size and high attenuation as detected by CT scan, surgery without multiple scans was an appropriate option. If this case showed single laterality, we would proceed to surgery without multiple scans. However, this case manifested as a bilateral adrenal tumor. We tried to investigate the possibility of leaving the adrenal gland on the one side and begin with surgical resection of the other, but eventually surgery on both sides was needed. This is the reason for undertaking multiple scans and the separate adrenalectomies.
Approximately 15% of adrenal incidentalomas have been reported to be bilateral [14, 16]. In bilateral cases, adrenocortical hypofunction could occur owing to the damage of normal adrenal glands by tumor masses; therefore, screening of the adrenal glands’ function has been recommended [14, 16]. Adrenocortical hypofunction was observed in our case during the preoperative diagnosis. Based on low serum cortisol levels and the results of the ACTH and CRH load test, secondary but not primary adrenal insufficiency was suspected as being the cause of adrenocortical hypofunction. In fact, the postoperative histological study revealed almost intact adrenal glands and bilateral adenomas, with cortisol-producing potential, which did not influence the HPA axis because of normal histological features of the zona fasciculata and reticularis and intact expression of DHEA-ST in the zona reticularis. Therefore, the adrenal insufficiency in this case might have been caused by the temporary use of an exogeneous glucocorticoid and not by direct damage to the adrenal glands by bilateral tumors.
Adrenal endothelial cysts are rare diseases, and cases complicated with adrenal neoplasms are known to be extremely rare [6, 8], with a female predominance and a right-sided prevalence [7], as observed in our case. The pathogenesis of an endothelial cyst with an adrenocortical adenoma has been speculated by a previous study: local circulatory failure by repeated cycles of thrombus formation and recanalization and blood flow communication to a preexisting hemangioma [6].
In our case, in addition to bilateral adrenocortical adenoma with endothelial cysts, morphologically and immunohistochemically confirmed diffuse adrenal hyperplasia of the zona glomerulosa was detected. Although serum aldosterone levels, serum renin activity, and blood pressure were all within the normal range, detailed examination of the resected adrenal gland revealed diffuse hyperplasia of the zona glomerulosa, which was diffusely positive for CYP11β2. High sodium intake in the modern lifestyle has been reported to diminish the area of zona glomerulosa with aging [20, 21] as the renin-angiotensin-aldosterone system (RAAS) is relatively suppressed [20]. Consequently, elderly people usually have a smaller area of zona glomerulosa. Hyperplasia of the zona glomerulosa was detected during excessive activation of the RAAS, which further results in secondary aldosteronism [20]. The patient in our study did not have diseases causing secondary aldosteronism, but one possibility for the activated RAAS was the use of empagliflozin, an SGLT2 inhibitor, which led to diffuse hyperplasia of the zona glomerulosa. Serum renin and aldosterone levels have been reported to increase significantly with SGLT2 inhibitor use within 1 month, which is associated with a decrease in extracellular fluid [22, 23]. Inconsistent results have been reported for the changes in RAAS in long-term treatments with SGLT2 inhibitors [24]. Although renin activity and aldosterone levels both were reported to normalize after 6 months of SGLT2 inhibitor treatment in some studies [22], increased RAAS activation after 24 weeks of SGLT2 inhibitor treatment was reported in another study [25]. Dehydration is one of the most frequent adverse events of SGLT2 inhibitor use [26, 27] due to the excretion of abundant urinary glucose. In our case, although serum renin and aldosterone levels were within the normal range, urine aldosterone level was above normal, and serum aldosterone level was close to the upper limit of the normal range. In addition, our patient had increased blood hemoglobin and hematocrit levels (15.0-15.7g/dL and 43.5%-46.4%, respectively), which suggest dehydration associated with SGLT2 inhibitor treatment before the operation, which returned to normal levels (13.9-14.5g/dL and 40.5%-42.6%, respectively) after discontinuation of the SGLT2 inhibitor post operation. In our study, surgical resection of the bilateral adrenal glands for the treatment of an adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine the morphology and histology of adrenal glands under SGLT2 inhibitor treatment, leading to unexpected findings of diffuse bilateral hyperplasia of the zona glomerulosa, with no functional changes in renin and aldosterone levels, and no increase in blood pressure. These results suggest the possibility of SGLT2 inhibitors having some effect on the zona glomerulosa of the adrenal gland; for instance, the latent loss of plasma volume caused by the SGLT2 inhibitor stimulating the zona glomerulosa chronically, leading to hyperplasia.
3. Conclusion
To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts coexisted, demonstrating the complexity and difficulty of preoperative diagnosis of bilateral adrenal incidentaloma. The adrenal mass in our case was not malignant, but a large tumor with cysts should be considered for resection because potential malignancy is ruled out by detailed histopathological evaluation of the lesions. In addition, surgical resection of bilateral adrenal glands for the treatment of adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine in detail the morphology and histology of the adrenal glands under SGLT2 inhibitor treatment, leading to an unexpected finding of diffuse bilateral hyperplasia of the zona glomerulosa in nonneoplastic adrenal glands, without clinically demonstrating primary aldosteronism. Therefore, we advocate a new hypothesis that SGLT2 inhibitors affect the zona glomerulosa of the adrenal gland; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of zona glomerulosa based on the data in this singular case. Because this can be confirmed only under limited conditions, additional case reports or animal model studies on adrenal gland histology under SGLT2 inhibition are warranted.
Acknowledgments
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Abbreviations
ACTH adrenocorticotropic hormone
CRH corticotropin-releasing hormone
CT computed tomography
CYP11β2 18-hydroxylase
DHEA-ST dehydroepiandrosterone-sulfotransferase
HPA hypothalamus-pituitary-adrenal
HSD3β 3β-hydroxysteroid dehydrogenase
H Hounsfield unit
MRI magnetic resonance imaging
PET positron emission tomography
RAAS renin-angiotensin-aldosterone system
SGLT2 sodium-glucose co-transport protein-2
Additional Information
Disclosure Summary: The authors have no conflicts of interest to report.
Data Availability
Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study. | EMPAGLIFLOZIN | DrugsGivenReaction | CC BY-NC-ND | 33381672 | 19,439,388 | 2021-02-01 |
What is the weight of the patient? | A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.
Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.
Adrenal cysts are rare cystic masses that are detected incidentally during autopsy in 0.06% of the population [1]. Approximately 6% of tumors detected as adrenal incidentalomas are adrenal cysts, as observed from the data of surgical series [2, 3]; however, a recent prospective study clarified that the incidence is much lower (< 1%) [4]. Adrenal cysts are classified as vascular or endothelial, epithelial, or parasitic [1, 5]. Pseudocysts are the most common type of adrenal cysts [6, 7]. Endothelial cysts associated with adrenal neoplasms are rare, with only a few reported cases [6, 8]. In addition, the cases of unilateral endothelial cysts and bilateral adrenal neoplasms have not been reported, to the best of our knowledge.
Primary aldosteronism is caused by the autonomous secretion of aldosterone owing to aldosterone-producing adenoma, multiple adrenocortical micronodules, and diffuse adrenocortical hyperplasia of the zona glomerulosa [9]. These conditions are known to be associated with high serum aldosterone and low renin levels, resulting in hypertension. However, we recently experienced a case of diffuse hyperplasia of the zona glomerulosa, positive for 18-hydroxylase: aldosterone synthase (CYP11β2), in which the patient had normal serum aldosterone levels, renin activity, and blood pressure.
Here, we report a rare case of bilateral adrenal adenomas with unilateral adrenal endothelial cysts. The possibility of sodium-glucose cotransporter protein 2 (SGLT2) inhibitor causing bilateral hyperplasia of the zona glomerulosa of the adrenal gland will also be discussed.
1. Case Presentation
A 65-year-old Japanese woman was referred to our hospital for characterization of the bilateral adrenal incidentaloma. At age 63, the patient was diagnosed with type 2 diabetes, which had been treated with diet and exercise therapy, and a gallstone identified by abdominal ultrasonography at a nearby clinic. Other than the diabetes and gallstone, she did not have any past medical history that needs specific mention. At age 64, the patient was administered an SGLT2 inhibitor, empagliflozin (10 mg/day), without any other medications and underwent abdominal ultrasonography for follow-up of the gallstone; however, adrenal masses were not identified at this point. At age 65, adrenal masses were incidentally identified during the abdominal ultrasonography during the follow-up examination of the gallstone. Consequently, subsequent plain abdominal computed tomography (CT) was performed, which revealed bilateral masses measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side (Fig. 1A). The right-sided mass was flat, with a small high-density spot, and heterogeneous, with a high-density (30-50 Hounsfield units [H]) and a low-density area (10-20 H). The left-sided mass was almost round with a relatively heterogeneous density (10-40 H).
Figure 1. Computed tomography (CT) scans of the right and left adrenal area. A, Plain CT showing a mass on the left and right sides (measuring 6.2 × 2.5 cm and 4.6 × 4.1 cm, respectively). B, Contrast-enhanced CT. C to F, Magnetic resonance imaging (MRI). C and D, T2-weighted images and images E, in phase and F, out of phase using chemical shift MRI.
The patient was admitted to our hospital for detailed examination. On admission, the patient did not present any signs or symptoms associated with excess adrenal cortical hormone levels or its deficiency. She had been taking an antidiabetic drug (empagliflozin, 10 mg/day) for approximately 1 year, and her diabetes was well controlled (fasting blood glucose: 116 mg/dL, glycated hemoglobin [hemoglobin A1c]: 6.9%). Between the third and first month prior to her introduction to our hospital, the patient used an ointment containing betamethasone butyrate propionate (exogenous glucocorticoid) for dermatitis. Physical examination revealed no significant findings. Clinical parameters were as follows: body height, 145.9 cm; body weight, 55.9 kg; blood pressure, 122/60 mm Hg; and heart rate, 60 beats/min. The laboratory data are presented in Table 1. The complete blood count and blood biochemistry tests were almost within the normal range.
Table 1. Laboratory findings of the patient
Peripheral blood Endocrinological data Load test
WBC 6060/mm3 (3300-8600) (Plasma) (CRH load)
RBC 462 × 104/mm3 (386-492) Epinephrine 24 pg/mL (0-100) ACTH 0 min 23.1 pg/mL
Hb 15.0 g/dL (11.6-14.8) Norepinephrine 304 pg/mL (100-450) 30 min 185.9 pg/mL
Ht 44.3% (35.1-44.4) Dopamine 10 pg/mL (0-20) 60 min 155.2 pg/mL
Plt 17.8 × 104/mm3 (15.8-34.8) Renin 2.3 ng/mL/h (0.3-5.4) 90 min 65.6 pg/mL
Aldosterone 149 pg/mL (29.9-159) 120 min 37.3 pg/mL
Biochemical data ARR 65 (< 200) Cortisol 0 min 4.5 μg/dL
T.P. 7.2 g/dL (6.6-8.1) ACTH (06:00) 32.0 pg/mL (7.2-63.3) 30 min 4.8 μg/dL
Albumin 4.2 g/dL (4.1-5.1) (12:00) 10.4 pg/mL 60 min 5.5 μg/dL
T.Bil 0.6 mg/dL (0.4-1.5) (18:00) 12.5 pg/mL 90 min 5.7 μg/dL
AST 25 U/L (13-30) (23:00) 13.6 pg/mL 120 min 5.5 μg/dL
ALT 29 U/L (7-23) Cortisol (06:00) 7.0 μg/dL (6.2-19.4)
LDH 248 U/L (124-222) (12:00) 4.4 μg/dL (ACTH load)
ALP 156 U/L (106-322) (18:00) 3.4 μg/dL Cortisol 0 min 4.3 μg/dL
rGTP 28 U/L (9-32) (23:00) 3.4 μg/dL 30 min 4.5 μg/dL
BUN 13 mg/dL (8-20) DHEA-S 96 μg/dL (12-133) 60 min 5.2 μg/dL
Crea 0.68 mg/dL (0.46-0.79) 90 min 5.7 μg/dL
Na 138 mEq/L (138-145) (Urine) 120 min 6.0 μg/dL
K 4.2 mEq/L (3.6-4.8) Epinephrine 8.2 μg/d (3.4-26.9)
Cl 105 mEq/L (101-108) Norepinephrine 133.3 μg/d (48.6-168.4)
Glucose 116 mg/dL (73-109) Dopamine 800.2 μg/d (365-961.5)
T.chol 177 mg/dL (142-220) Aldosterone 11 μg/d (0-10)
HbA1c 6.9% (4.9-6.2) Cortisol 75.3 μg/d (11.2-80.3)
sIL-2R 325 U/mL (121-613)
Reference ranges are in parentheses.
Abbreviations: ACTH, adrenocorticotropin; ALP, alkaline phosphatase; ALT, alanine transferase; ARR, aldosterone/renin ratio; AST, aspartate transaminase; BUN, blood urea nitrogen; Cl, chlorine; Crea, creatinine; DHEA-S, dehydroepiandrosterone-sulfate; Hb, hemoglobin; HbA1c, glycated hemoglobin; Ht, hematocrit; K, potassium; LDH, lactate dehydrogenase; Na, natrium; Plt, platelets; RBC, red blood cells; rGTP, γ-glutamyl transferase; sIL-2R, soluble interleukin-2 receptor; T.Bil, total bilirubin; T.chol, total cholesterol; T.P, total protein; WBC, white blood cells.
Endocrinological data are also presented in Table 1. Blood and 24-hour urine catecholamines were within the normal range. Plasma aldosterone concentration of 149 pg/mL, plasma renin activity of 2.3 ng/mL/h, and aldosterone/renin ratio of 65 were within the normal range. Urine aldosterone level (11 µg/day) was slightly elevated. Cortisol and adrenocorticotropin (ACTH) levels early in the morning were 5.3 µg/dL and 15.8 pg/mL (at an outpatient clinic) and 7.0 µg/dL and 32.0 pg/mL (after hospitalization), respectively (cortisol and ACTH levels were measured by Eclusys Cortisol II and Eclusys ACTH; reference values were 6.2-19.4 µg/dL and 7.2-63.3 pg/mL, respectively [Roche Diagnostics Inc]). In addition, the cortisol levels at 12:00, 18:00, and 23:00 h were 4.4, 3.4, and 3.4 µg/dL, respectively. Although adrenal insufficiency could be caused by prior exogenous corticosteroid use, load test with adrenocorticotropic hormone (ACTH: tetracosactide acetate 250 μg) was performed and the ACTH-stimulated cortisol response was low (cortisol less than 18 μg/dL as a basis for adrenal insufficiency). Load test with corticotropin-releasing hormone (CRH:corticorelin 100 μg) was also performed and the CRH-stimulated ACTH response was intact, but the cortisol response was low. These results indicated secondary adrenocortical hypofunction, probably due to the ointment containing glucocorticoid.
In addition to a plain CT, contrast-enhanced CT was also performed (Fig. 1B). The bilateral tumor showed a clear margin. Cystic regions were clearly detected in the right adrenal region. Magnetic resonance imaging (MRI) revealed some encapsulated fluid lesions in the right-sided mass with high signal intensity on T2-weighted images (Fig. 1C and 1D), suggesting the possibility of cysts or hemangiomas. The left-sided mass showed higher signal intensity than the liver on T2-weighted images. On chemical shift MRI (Fig. 1E and 1F) of the adrenal glands, the loss of signal intensity was not detected in out-of-phase imaging when compared with that of the spleen, suggesting the possibility of malignancy rather than adenoma [10]. However, on 18F-fluorodeoxyglucose positron emission tomography (PET), no suspicious malignant lesion was detected.
The patient underwent laparoscopic right adrenalectomy because the possibility of malignancy could not be excluded. The resected right adrenal gland weighed 45 g, and the tumor measured 45 × 40 × 32 mm. Representative histological findings are illustrated in Fig. 2A and 2B. The tumor was composed of compact cells with eosinophilic cytoplasm and scattered foci of clear cells. Based on the Weiss criteria, the tumor was diagnosed as an adrenocortical adenoma, and the cysts were detected adjacent to the tumor. Most of the right adrenal glands remained intact.
Figure 2. Photomicrograph of the resected tumors and adrenal glands (hematoxylin-eosin stain). A, Intact adrenal tissue (blue arrows) and tumor with a cyst in the right side. B, Enlarged view of the dotted region A. C, intact adrenal tissue (blue arrows) and tumor in the left side. D, Enlarged view of the dotted region C.
While the characteristics of the left adrenal lesion could not be determined, the left adrenal gland had a different shape from the right adrenal mass, and the possibility of malignancy could not be completely excluded. Therefore, the patient subsequently underwent laparoscopic left adrenalectomy. The resected left adrenal gland weighed 54 g, and the tumor measured 65 × 50 × 30 mm. Representative histological findings are illustrated in Fig. 2C and 2D. The histological features of the tumor in the left adrenal gland were similar to those in the right adrenal gland. The tumor on the left side was also diagnosed as an adrenocortical adenoma. No cysts were discernible in the left resected specimen, and most of the left adrenal glands remained intact.
In addition to the hematoxylin-eosin stain, we immunolocalized steroidogenic enzymes in both the resected adrenal glands (Figs. 3-5). In both tumors, immunoreactivity of 3β-hydroxysteroid dehydrogenase (HSD3β), 17α-hydroxylase, and 11β-hydroxylase (Fig. 3A and 3D) was diffusely detected but that of CYP11β2 [9, 11] was not (Fig. 3B and 3E). These results demonstrate that the tumor cells could produce cortisol but not aldosterone. Immunoreactivity of dehydroepiandrosterone-sulfotransferase (DHEA-ST) in the zona reticularis of the attached nonneoplastic adrenal cortex, which reflects the long-term dynamics of the hypothalamus-pituitary-adrenal (HPA) axis, was within normal limits (Fig. 3C and 3F). Therefore, cortisol produced by these tumors did not affect the HPA axis in the patient. Ki-67 labeling indices were 2.5% in the right adrenal tumor and less than 1% in the left adrenal tumor. The right-sided cysts were diagnosed as endothelial cysts because the monolayer lining cells were positive for CD31 immunoreactivity (Fig. 4). The nonneoplastic adrenal glands adjacent to the tumors on both sides had similar pathological features: morphologically hyperplastic in the zona glomerulosa (immunohistochemically positive for HSD3β and CYP11β2 [Fig. 3B and 3E and Fig. 5]) [9]. The final diagnosis of the resected adrenal glands following detailed analyses of steroidogenesis was that of a bilateral nonfunctional adrenocortical adenoma with cortisol-producing ability, with endothelial cyst formation and bilateral diffuse hyperplasia of the zona glomerulosa in the adjacent nonneoplastic adrenal glands.
Figure 3. Photomicrograph of the resected tumors and adrenal glands in A to C, the right side and D to F, the left side. A and D, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). The zona fasciculata and zona reticularis of the adrenal glands were positive for CYP11β1. Tumors were also positive for CYP11β1. B and E, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). Lined positivity for CYP11β2 of the zona glomerulosa was detected (blue arrows). Tumors were negative for CYP11β2. C and F, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST). The zona reticularis of the adrenal glands was positive for DHEA-ST. Tumors were negative for DHEA-ST.
Figure 4. Photomicrograph of the right-sided cystic region (immunohistochemical labeling for CD31). The monolayer lining cells of the cyst wall were CD31 positive, indicating endothelial cysts.
Figure 5. Photomicrograph of the resected intact adrenal tissue. Morphologically hyperplastic feature was detected in the zona glomerulosa. A, Hematoxylin-eosin staining. B, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). C, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). D, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST).
The postoperative course of the patient was uneventful. Hydrocortisone replacement was continued. Fludrocortisone was not administered according to a clinical practice guideline on primary adrenal insufficiency by the Japan Endocrine Society [12]. However, the clinical practice guideline of the Endocrine Society recommends mineral corticoid replacement with fludrocortisone and no restriction on salt intake [13]. Her blood pressure was 102 to 120/56 to 80 mm Hg. The patient’s blood biochemistry data were almost within the normal range. Fasting blood glucose and hemoglobin A1c levels were improved, reaching 100 mg/dL and 6.5%, respectively, without the administration of SGLT2 inhibitor or other diabetic medications (empagliflozin was stopped before the first surgery). This remission of diabetes might be caused by the reduction of body weight and cessation of the exogenous glucocorticoid.
2. Discussion
In our case, the adrenal glands showed relatively large bilateral adrenal incidentalomas (measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side) and unilateral cysts on the right side. In addition, these tumor masses showed a density of 30 to 50 H on the right side and 10 to 40 H on the left side on CT. To date, 24% of adrenal incidentalomas measuring more than 4 cm in diameter have been reported as being malignant lesions, with 90% of adrenal carcinomas having been reported to be larger than 4 cm in diameter [14]. The lipid content of the adrenal mass results in low attenuation on CT, which enables the distinction of adenomas from nonadenomas; adenomas have low attenuation (≤ 10 H) on CT [14]. Moreover, discerning the malignancy of the adrenal cystic lesions precisely, without histological diagnosis, is difficult [15]. Furthermore, the prevalence of benign adrenal cortical adenomas has been reported to increase with age [14]. In our case, surgical excision was based on the following conditions: surgical removal should be considered for nonfunctional adrenal masses measuring more than 4 cm unless there is a clear benign cause [16, 17] and should also be considered for masses measuring more than 4.6 cm or more than 20 H on CT [18]. In addition, because adrenal carcinomas could be associated with benign-appearing cysts, whole-specimen exploration of resected tissues is definitively recommended to rule out malignancy [19].
We performed multiple scans: CT, MRI, and PET. When an adrenal tumor has a large size and high attenuation as detected by CT scan, surgery without multiple scans was an appropriate option. If this case showed single laterality, we would proceed to surgery without multiple scans. However, this case manifested as a bilateral adrenal tumor. We tried to investigate the possibility of leaving the adrenal gland on the one side and begin with surgical resection of the other, but eventually surgery on both sides was needed. This is the reason for undertaking multiple scans and the separate adrenalectomies.
Approximately 15% of adrenal incidentalomas have been reported to be bilateral [14, 16]. In bilateral cases, adrenocortical hypofunction could occur owing to the damage of normal adrenal glands by tumor masses; therefore, screening of the adrenal glands’ function has been recommended [14, 16]. Adrenocortical hypofunction was observed in our case during the preoperative diagnosis. Based on low serum cortisol levels and the results of the ACTH and CRH load test, secondary but not primary adrenal insufficiency was suspected as being the cause of adrenocortical hypofunction. In fact, the postoperative histological study revealed almost intact adrenal glands and bilateral adenomas, with cortisol-producing potential, which did not influence the HPA axis because of normal histological features of the zona fasciculata and reticularis and intact expression of DHEA-ST in the zona reticularis. Therefore, the adrenal insufficiency in this case might have been caused by the temporary use of an exogeneous glucocorticoid and not by direct damage to the adrenal glands by bilateral tumors.
Adrenal endothelial cysts are rare diseases, and cases complicated with adrenal neoplasms are known to be extremely rare [6, 8], with a female predominance and a right-sided prevalence [7], as observed in our case. The pathogenesis of an endothelial cyst with an adrenocortical adenoma has been speculated by a previous study: local circulatory failure by repeated cycles of thrombus formation and recanalization and blood flow communication to a preexisting hemangioma [6].
In our case, in addition to bilateral adrenocortical adenoma with endothelial cysts, morphologically and immunohistochemically confirmed diffuse adrenal hyperplasia of the zona glomerulosa was detected. Although serum aldosterone levels, serum renin activity, and blood pressure were all within the normal range, detailed examination of the resected adrenal gland revealed diffuse hyperplasia of the zona glomerulosa, which was diffusely positive for CYP11β2. High sodium intake in the modern lifestyle has been reported to diminish the area of zona glomerulosa with aging [20, 21] as the renin-angiotensin-aldosterone system (RAAS) is relatively suppressed [20]. Consequently, elderly people usually have a smaller area of zona glomerulosa. Hyperplasia of the zona glomerulosa was detected during excessive activation of the RAAS, which further results in secondary aldosteronism [20]. The patient in our study did not have diseases causing secondary aldosteronism, but one possibility for the activated RAAS was the use of empagliflozin, an SGLT2 inhibitor, which led to diffuse hyperplasia of the zona glomerulosa. Serum renin and aldosterone levels have been reported to increase significantly with SGLT2 inhibitor use within 1 month, which is associated with a decrease in extracellular fluid [22, 23]. Inconsistent results have been reported for the changes in RAAS in long-term treatments with SGLT2 inhibitors [24]. Although renin activity and aldosterone levels both were reported to normalize after 6 months of SGLT2 inhibitor treatment in some studies [22], increased RAAS activation after 24 weeks of SGLT2 inhibitor treatment was reported in another study [25]. Dehydration is one of the most frequent adverse events of SGLT2 inhibitor use [26, 27] due to the excretion of abundant urinary glucose. In our case, although serum renin and aldosterone levels were within the normal range, urine aldosterone level was above normal, and serum aldosterone level was close to the upper limit of the normal range. In addition, our patient had increased blood hemoglobin and hematocrit levels (15.0-15.7g/dL and 43.5%-46.4%, respectively), which suggest dehydration associated with SGLT2 inhibitor treatment before the operation, which returned to normal levels (13.9-14.5g/dL and 40.5%-42.6%, respectively) after discontinuation of the SGLT2 inhibitor post operation. In our study, surgical resection of the bilateral adrenal glands for the treatment of an adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine the morphology and histology of adrenal glands under SGLT2 inhibitor treatment, leading to unexpected findings of diffuse bilateral hyperplasia of the zona glomerulosa, with no functional changes in renin and aldosterone levels, and no increase in blood pressure. These results suggest the possibility of SGLT2 inhibitors having some effect on the zona glomerulosa of the adrenal gland; for instance, the latent loss of plasma volume caused by the SGLT2 inhibitor stimulating the zona glomerulosa chronically, leading to hyperplasia.
3. Conclusion
To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts coexisted, demonstrating the complexity and difficulty of preoperative diagnosis of bilateral adrenal incidentaloma. The adrenal mass in our case was not malignant, but a large tumor with cysts should be considered for resection because potential malignancy is ruled out by detailed histopathological evaluation of the lesions. In addition, surgical resection of bilateral adrenal glands for the treatment of adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine in detail the morphology and histology of the adrenal glands under SGLT2 inhibitor treatment, leading to an unexpected finding of diffuse bilateral hyperplasia of the zona glomerulosa in nonneoplastic adrenal glands, without clinically demonstrating primary aldosteronism. Therefore, we advocate a new hypothesis that SGLT2 inhibitors affect the zona glomerulosa of the adrenal gland; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of zona glomerulosa based on the data in this singular case. Because this can be confirmed only under limited conditions, additional case reports or animal model studies on adrenal gland histology under SGLT2 inhibition are warranted.
Acknowledgments
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Abbreviations
ACTH adrenocorticotropic hormone
CRH corticotropin-releasing hormone
CT computed tomography
CYP11β2 18-hydroxylase
DHEA-ST dehydroepiandrosterone-sulfotransferase
HPA hypothalamus-pituitary-adrenal
HSD3β 3β-hydroxysteroid dehydrogenase
H Hounsfield unit
MRI magnetic resonance imaging
PET positron emission tomography
RAAS renin-angiotensin-aldosterone system
SGLT2 sodium-glucose co-transport protein-2
Additional Information
Disclosure Summary: The authors have no conflicts of interest to report.
Data Availability
Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study. | 55.9 kg. | Weight | CC BY-NC-ND | 33381672 | 19,439,388 | 2021-02-01 |
What was the dosage of drug 'EMPAGLIFLOZIN'? | A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.
Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.
Adrenal cysts are rare cystic masses that are detected incidentally during autopsy in 0.06% of the population [1]. Approximately 6% of tumors detected as adrenal incidentalomas are adrenal cysts, as observed from the data of surgical series [2, 3]; however, a recent prospective study clarified that the incidence is much lower (< 1%) [4]. Adrenal cysts are classified as vascular or endothelial, epithelial, or parasitic [1, 5]. Pseudocysts are the most common type of adrenal cysts [6, 7]. Endothelial cysts associated with adrenal neoplasms are rare, with only a few reported cases [6, 8]. In addition, the cases of unilateral endothelial cysts and bilateral adrenal neoplasms have not been reported, to the best of our knowledge.
Primary aldosteronism is caused by the autonomous secretion of aldosterone owing to aldosterone-producing adenoma, multiple adrenocortical micronodules, and diffuse adrenocortical hyperplasia of the zona glomerulosa [9]. These conditions are known to be associated with high serum aldosterone and low renin levels, resulting in hypertension. However, we recently experienced a case of diffuse hyperplasia of the zona glomerulosa, positive for 18-hydroxylase: aldosterone synthase (CYP11β2), in which the patient had normal serum aldosterone levels, renin activity, and blood pressure.
Here, we report a rare case of bilateral adrenal adenomas with unilateral adrenal endothelial cysts. The possibility of sodium-glucose cotransporter protein 2 (SGLT2) inhibitor causing bilateral hyperplasia of the zona glomerulosa of the adrenal gland will also be discussed.
1. Case Presentation
A 65-year-old Japanese woman was referred to our hospital for characterization of the bilateral adrenal incidentaloma. At age 63, the patient was diagnosed with type 2 diabetes, which had been treated with diet and exercise therapy, and a gallstone identified by abdominal ultrasonography at a nearby clinic. Other than the diabetes and gallstone, she did not have any past medical history that needs specific mention. At age 64, the patient was administered an SGLT2 inhibitor, empagliflozin (10 mg/day), without any other medications and underwent abdominal ultrasonography for follow-up of the gallstone; however, adrenal masses were not identified at this point. At age 65, adrenal masses were incidentally identified during the abdominal ultrasonography during the follow-up examination of the gallstone. Consequently, subsequent plain abdominal computed tomography (CT) was performed, which revealed bilateral masses measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side (Fig. 1A). The right-sided mass was flat, with a small high-density spot, and heterogeneous, with a high-density (30-50 Hounsfield units [H]) and a low-density area (10-20 H). The left-sided mass was almost round with a relatively heterogeneous density (10-40 H).
Figure 1. Computed tomography (CT) scans of the right and left adrenal area. A, Plain CT showing a mass on the left and right sides (measuring 6.2 × 2.5 cm and 4.6 × 4.1 cm, respectively). B, Contrast-enhanced CT. C to F, Magnetic resonance imaging (MRI). C and D, T2-weighted images and images E, in phase and F, out of phase using chemical shift MRI.
The patient was admitted to our hospital for detailed examination. On admission, the patient did not present any signs or symptoms associated with excess adrenal cortical hormone levels or its deficiency. She had been taking an antidiabetic drug (empagliflozin, 10 mg/day) for approximately 1 year, and her diabetes was well controlled (fasting blood glucose: 116 mg/dL, glycated hemoglobin [hemoglobin A1c]: 6.9%). Between the third and first month prior to her introduction to our hospital, the patient used an ointment containing betamethasone butyrate propionate (exogenous glucocorticoid) for dermatitis. Physical examination revealed no significant findings. Clinical parameters were as follows: body height, 145.9 cm; body weight, 55.9 kg; blood pressure, 122/60 mm Hg; and heart rate, 60 beats/min. The laboratory data are presented in Table 1. The complete blood count and blood biochemistry tests were almost within the normal range.
Table 1. Laboratory findings of the patient
Peripheral blood Endocrinological data Load test
WBC 6060/mm3 (3300-8600) (Plasma) (CRH load)
RBC 462 × 104/mm3 (386-492) Epinephrine 24 pg/mL (0-100) ACTH 0 min 23.1 pg/mL
Hb 15.0 g/dL (11.6-14.8) Norepinephrine 304 pg/mL (100-450) 30 min 185.9 pg/mL
Ht 44.3% (35.1-44.4) Dopamine 10 pg/mL (0-20) 60 min 155.2 pg/mL
Plt 17.8 × 104/mm3 (15.8-34.8) Renin 2.3 ng/mL/h (0.3-5.4) 90 min 65.6 pg/mL
Aldosterone 149 pg/mL (29.9-159) 120 min 37.3 pg/mL
Biochemical data ARR 65 (< 200) Cortisol 0 min 4.5 μg/dL
T.P. 7.2 g/dL (6.6-8.1) ACTH (06:00) 32.0 pg/mL (7.2-63.3) 30 min 4.8 μg/dL
Albumin 4.2 g/dL (4.1-5.1) (12:00) 10.4 pg/mL 60 min 5.5 μg/dL
T.Bil 0.6 mg/dL (0.4-1.5) (18:00) 12.5 pg/mL 90 min 5.7 μg/dL
AST 25 U/L (13-30) (23:00) 13.6 pg/mL 120 min 5.5 μg/dL
ALT 29 U/L (7-23) Cortisol (06:00) 7.0 μg/dL (6.2-19.4)
LDH 248 U/L (124-222) (12:00) 4.4 μg/dL (ACTH load)
ALP 156 U/L (106-322) (18:00) 3.4 μg/dL Cortisol 0 min 4.3 μg/dL
rGTP 28 U/L (9-32) (23:00) 3.4 μg/dL 30 min 4.5 μg/dL
BUN 13 mg/dL (8-20) DHEA-S 96 μg/dL (12-133) 60 min 5.2 μg/dL
Crea 0.68 mg/dL (0.46-0.79) 90 min 5.7 μg/dL
Na 138 mEq/L (138-145) (Urine) 120 min 6.0 μg/dL
K 4.2 mEq/L (3.6-4.8) Epinephrine 8.2 μg/d (3.4-26.9)
Cl 105 mEq/L (101-108) Norepinephrine 133.3 μg/d (48.6-168.4)
Glucose 116 mg/dL (73-109) Dopamine 800.2 μg/d (365-961.5)
T.chol 177 mg/dL (142-220) Aldosterone 11 μg/d (0-10)
HbA1c 6.9% (4.9-6.2) Cortisol 75.3 μg/d (11.2-80.3)
sIL-2R 325 U/mL (121-613)
Reference ranges are in parentheses.
Abbreviations: ACTH, adrenocorticotropin; ALP, alkaline phosphatase; ALT, alanine transferase; ARR, aldosterone/renin ratio; AST, aspartate transaminase; BUN, blood urea nitrogen; Cl, chlorine; Crea, creatinine; DHEA-S, dehydroepiandrosterone-sulfate; Hb, hemoglobin; HbA1c, glycated hemoglobin; Ht, hematocrit; K, potassium; LDH, lactate dehydrogenase; Na, natrium; Plt, platelets; RBC, red blood cells; rGTP, γ-glutamyl transferase; sIL-2R, soluble interleukin-2 receptor; T.Bil, total bilirubin; T.chol, total cholesterol; T.P, total protein; WBC, white blood cells.
Endocrinological data are also presented in Table 1. Blood and 24-hour urine catecholamines were within the normal range. Plasma aldosterone concentration of 149 pg/mL, plasma renin activity of 2.3 ng/mL/h, and aldosterone/renin ratio of 65 were within the normal range. Urine aldosterone level (11 µg/day) was slightly elevated. Cortisol and adrenocorticotropin (ACTH) levels early in the morning were 5.3 µg/dL and 15.8 pg/mL (at an outpatient clinic) and 7.0 µg/dL and 32.0 pg/mL (after hospitalization), respectively (cortisol and ACTH levels were measured by Eclusys Cortisol II and Eclusys ACTH; reference values were 6.2-19.4 µg/dL and 7.2-63.3 pg/mL, respectively [Roche Diagnostics Inc]). In addition, the cortisol levels at 12:00, 18:00, and 23:00 h were 4.4, 3.4, and 3.4 µg/dL, respectively. Although adrenal insufficiency could be caused by prior exogenous corticosteroid use, load test with adrenocorticotropic hormone (ACTH: tetracosactide acetate 250 μg) was performed and the ACTH-stimulated cortisol response was low (cortisol less than 18 μg/dL as a basis for adrenal insufficiency). Load test with corticotropin-releasing hormone (CRH:corticorelin 100 μg) was also performed and the CRH-stimulated ACTH response was intact, but the cortisol response was low. These results indicated secondary adrenocortical hypofunction, probably due to the ointment containing glucocorticoid.
In addition to a plain CT, contrast-enhanced CT was also performed (Fig. 1B). The bilateral tumor showed a clear margin. Cystic regions were clearly detected in the right adrenal region. Magnetic resonance imaging (MRI) revealed some encapsulated fluid lesions in the right-sided mass with high signal intensity on T2-weighted images (Fig. 1C and 1D), suggesting the possibility of cysts or hemangiomas. The left-sided mass showed higher signal intensity than the liver on T2-weighted images. On chemical shift MRI (Fig. 1E and 1F) of the adrenal glands, the loss of signal intensity was not detected in out-of-phase imaging when compared with that of the spleen, suggesting the possibility of malignancy rather than adenoma [10]. However, on 18F-fluorodeoxyglucose positron emission tomography (PET), no suspicious malignant lesion was detected.
The patient underwent laparoscopic right adrenalectomy because the possibility of malignancy could not be excluded. The resected right adrenal gland weighed 45 g, and the tumor measured 45 × 40 × 32 mm. Representative histological findings are illustrated in Fig. 2A and 2B. The tumor was composed of compact cells with eosinophilic cytoplasm and scattered foci of clear cells. Based on the Weiss criteria, the tumor was diagnosed as an adrenocortical adenoma, and the cysts were detected adjacent to the tumor. Most of the right adrenal glands remained intact.
Figure 2. Photomicrograph of the resected tumors and adrenal glands (hematoxylin-eosin stain). A, Intact adrenal tissue (blue arrows) and tumor with a cyst in the right side. B, Enlarged view of the dotted region A. C, intact adrenal tissue (blue arrows) and tumor in the left side. D, Enlarged view of the dotted region C.
While the characteristics of the left adrenal lesion could not be determined, the left adrenal gland had a different shape from the right adrenal mass, and the possibility of malignancy could not be completely excluded. Therefore, the patient subsequently underwent laparoscopic left adrenalectomy. The resected left adrenal gland weighed 54 g, and the tumor measured 65 × 50 × 30 mm. Representative histological findings are illustrated in Fig. 2C and 2D. The histological features of the tumor in the left adrenal gland were similar to those in the right adrenal gland. The tumor on the left side was also diagnosed as an adrenocortical adenoma. No cysts were discernible in the left resected specimen, and most of the left adrenal glands remained intact.
In addition to the hematoxylin-eosin stain, we immunolocalized steroidogenic enzymes in both the resected adrenal glands (Figs. 3-5). In both tumors, immunoreactivity of 3β-hydroxysteroid dehydrogenase (HSD3β), 17α-hydroxylase, and 11β-hydroxylase (Fig. 3A and 3D) was diffusely detected but that of CYP11β2 [9, 11] was not (Fig. 3B and 3E). These results demonstrate that the tumor cells could produce cortisol but not aldosterone. Immunoreactivity of dehydroepiandrosterone-sulfotransferase (DHEA-ST) in the zona reticularis of the attached nonneoplastic adrenal cortex, which reflects the long-term dynamics of the hypothalamus-pituitary-adrenal (HPA) axis, was within normal limits (Fig. 3C and 3F). Therefore, cortisol produced by these tumors did not affect the HPA axis in the patient. Ki-67 labeling indices were 2.5% in the right adrenal tumor and less than 1% in the left adrenal tumor. The right-sided cysts were diagnosed as endothelial cysts because the monolayer lining cells were positive for CD31 immunoreactivity (Fig. 4). The nonneoplastic adrenal glands adjacent to the tumors on both sides had similar pathological features: morphologically hyperplastic in the zona glomerulosa (immunohistochemically positive for HSD3β and CYP11β2 [Fig. 3B and 3E and Fig. 5]) [9]. The final diagnosis of the resected adrenal glands following detailed analyses of steroidogenesis was that of a bilateral nonfunctional adrenocortical adenoma with cortisol-producing ability, with endothelial cyst formation and bilateral diffuse hyperplasia of the zona glomerulosa in the adjacent nonneoplastic adrenal glands.
Figure 3. Photomicrograph of the resected tumors and adrenal glands in A to C, the right side and D to F, the left side. A and D, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). The zona fasciculata and zona reticularis of the adrenal glands were positive for CYP11β1. Tumors were also positive for CYP11β1. B and E, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). Lined positivity for CYP11β2 of the zona glomerulosa was detected (blue arrows). Tumors were negative for CYP11β2. C and F, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST). The zona reticularis of the adrenal glands was positive for DHEA-ST. Tumors were negative for DHEA-ST.
Figure 4. Photomicrograph of the right-sided cystic region (immunohistochemical labeling for CD31). The monolayer lining cells of the cyst wall were CD31 positive, indicating endothelial cysts.
Figure 5. Photomicrograph of the resected intact adrenal tissue. Morphologically hyperplastic feature was detected in the zona glomerulosa. A, Hematoxylin-eosin staining. B, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). C, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). D, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST).
The postoperative course of the patient was uneventful. Hydrocortisone replacement was continued. Fludrocortisone was not administered according to a clinical practice guideline on primary adrenal insufficiency by the Japan Endocrine Society [12]. However, the clinical practice guideline of the Endocrine Society recommends mineral corticoid replacement with fludrocortisone and no restriction on salt intake [13]. Her blood pressure was 102 to 120/56 to 80 mm Hg. The patient’s blood biochemistry data were almost within the normal range. Fasting blood glucose and hemoglobin A1c levels were improved, reaching 100 mg/dL and 6.5%, respectively, without the administration of SGLT2 inhibitor or other diabetic medications (empagliflozin was stopped before the first surgery). This remission of diabetes might be caused by the reduction of body weight and cessation of the exogenous glucocorticoid.
2. Discussion
In our case, the adrenal glands showed relatively large bilateral adrenal incidentalomas (measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side) and unilateral cysts on the right side. In addition, these tumor masses showed a density of 30 to 50 H on the right side and 10 to 40 H on the left side on CT. To date, 24% of adrenal incidentalomas measuring more than 4 cm in diameter have been reported as being malignant lesions, with 90% of adrenal carcinomas having been reported to be larger than 4 cm in diameter [14]. The lipid content of the adrenal mass results in low attenuation on CT, which enables the distinction of adenomas from nonadenomas; adenomas have low attenuation (≤ 10 H) on CT [14]. Moreover, discerning the malignancy of the adrenal cystic lesions precisely, without histological diagnosis, is difficult [15]. Furthermore, the prevalence of benign adrenal cortical adenomas has been reported to increase with age [14]. In our case, surgical excision was based on the following conditions: surgical removal should be considered for nonfunctional adrenal masses measuring more than 4 cm unless there is a clear benign cause [16, 17] and should also be considered for masses measuring more than 4.6 cm or more than 20 H on CT [18]. In addition, because adrenal carcinomas could be associated with benign-appearing cysts, whole-specimen exploration of resected tissues is definitively recommended to rule out malignancy [19].
We performed multiple scans: CT, MRI, and PET. When an adrenal tumor has a large size and high attenuation as detected by CT scan, surgery without multiple scans was an appropriate option. If this case showed single laterality, we would proceed to surgery without multiple scans. However, this case manifested as a bilateral adrenal tumor. We tried to investigate the possibility of leaving the adrenal gland on the one side and begin with surgical resection of the other, but eventually surgery on both sides was needed. This is the reason for undertaking multiple scans and the separate adrenalectomies.
Approximately 15% of adrenal incidentalomas have been reported to be bilateral [14, 16]. In bilateral cases, adrenocortical hypofunction could occur owing to the damage of normal adrenal glands by tumor masses; therefore, screening of the adrenal glands’ function has been recommended [14, 16]. Adrenocortical hypofunction was observed in our case during the preoperative diagnosis. Based on low serum cortisol levels and the results of the ACTH and CRH load test, secondary but not primary adrenal insufficiency was suspected as being the cause of adrenocortical hypofunction. In fact, the postoperative histological study revealed almost intact adrenal glands and bilateral adenomas, with cortisol-producing potential, which did not influence the HPA axis because of normal histological features of the zona fasciculata and reticularis and intact expression of DHEA-ST in the zona reticularis. Therefore, the adrenal insufficiency in this case might have been caused by the temporary use of an exogeneous glucocorticoid and not by direct damage to the adrenal glands by bilateral tumors.
Adrenal endothelial cysts are rare diseases, and cases complicated with adrenal neoplasms are known to be extremely rare [6, 8], with a female predominance and a right-sided prevalence [7], as observed in our case. The pathogenesis of an endothelial cyst with an adrenocortical adenoma has been speculated by a previous study: local circulatory failure by repeated cycles of thrombus formation and recanalization and blood flow communication to a preexisting hemangioma [6].
In our case, in addition to bilateral adrenocortical adenoma with endothelial cysts, morphologically and immunohistochemically confirmed diffuse adrenal hyperplasia of the zona glomerulosa was detected. Although serum aldosterone levels, serum renin activity, and blood pressure were all within the normal range, detailed examination of the resected adrenal gland revealed diffuse hyperplasia of the zona glomerulosa, which was diffusely positive for CYP11β2. High sodium intake in the modern lifestyle has been reported to diminish the area of zona glomerulosa with aging [20, 21] as the renin-angiotensin-aldosterone system (RAAS) is relatively suppressed [20]. Consequently, elderly people usually have a smaller area of zona glomerulosa. Hyperplasia of the zona glomerulosa was detected during excessive activation of the RAAS, which further results in secondary aldosteronism [20]. The patient in our study did not have diseases causing secondary aldosteronism, but one possibility for the activated RAAS was the use of empagliflozin, an SGLT2 inhibitor, which led to diffuse hyperplasia of the zona glomerulosa. Serum renin and aldosterone levels have been reported to increase significantly with SGLT2 inhibitor use within 1 month, which is associated with a decrease in extracellular fluid [22, 23]. Inconsistent results have been reported for the changes in RAAS in long-term treatments with SGLT2 inhibitors [24]. Although renin activity and aldosterone levels both were reported to normalize after 6 months of SGLT2 inhibitor treatment in some studies [22], increased RAAS activation after 24 weeks of SGLT2 inhibitor treatment was reported in another study [25]. Dehydration is one of the most frequent adverse events of SGLT2 inhibitor use [26, 27] due to the excretion of abundant urinary glucose. In our case, although serum renin and aldosterone levels were within the normal range, urine aldosterone level was above normal, and serum aldosterone level was close to the upper limit of the normal range. In addition, our patient had increased blood hemoglobin and hematocrit levels (15.0-15.7g/dL and 43.5%-46.4%, respectively), which suggest dehydration associated with SGLT2 inhibitor treatment before the operation, which returned to normal levels (13.9-14.5g/dL and 40.5%-42.6%, respectively) after discontinuation of the SGLT2 inhibitor post operation. In our study, surgical resection of the bilateral adrenal glands for the treatment of an adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine the morphology and histology of adrenal glands under SGLT2 inhibitor treatment, leading to unexpected findings of diffuse bilateral hyperplasia of the zona glomerulosa, with no functional changes in renin and aldosterone levels, and no increase in blood pressure. These results suggest the possibility of SGLT2 inhibitors having some effect on the zona glomerulosa of the adrenal gland; for instance, the latent loss of plasma volume caused by the SGLT2 inhibitor stimulating the zona glomerulosa chronically, leading to hyperplasia.
3. Conclusion
To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts coexisted, demonstrating the complexity and difficulty of preoperative diagnosis of bilateral adrenal incidentaloma. The adrenal mass in our case was not malignant, but a large tumor with cysts should be considered for resection because potential malignancy is ruled out by detailed histopathological evaluation of the lesions. In addition, surgical resection of bilateral adrenal glands for the treatment of adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine in detail the morphology and histology of the adrenal glands under SGLT2 inhibitor treatment, leading to an unexpected finding of diffuse bilateral hyperplasia of the zona glomerulosa in nonneoplastic adrenal glands, without clinically demonstrating primary aldosteronism. Therefore, we advocate a new hypothesis that SGLT2 inhibitors affect the zona glomerulosa of the adrenal gland; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of zona glomerulosa based on the data in this singular case. Because this can be confirmed only under limited conditions, additional case reports or animal model studies on adrenal gland histology under SGLT2 inhibition are warranted.
Acknowledgments
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Abbreviations
ACTH adrenocorticotropic hormone
CRH corticotropin-releasing hormone
CT computed tomography
CYP11β2 18-hydroxylase
DHEA-ST dehydroepiandrosterone-sulfotransferase
HPA hypothalamus-pituitary-adrenal
HSD3β 3β-hydroxysteroid dehydrogenase
H Hounsfield unit
MRI magnetic resonance imaging
PET positron emission tomography
RAAS renin-angiotensin-aldosterone system
SGLT2 sodium-glucose co-transport protein-2
Additional Information
Disclosure Summary: The authors have no conflicts of interest to report.
Data Availability
Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study. | 10 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33381672 | 19,439,388 | 2021-02-01 |
What was the outcome of reaction 'Adrenal cyst'? | A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.
Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.
Adrenal cysts are rare cystic masses that are detected incidentally during autopsy in 0.06% of the population [1]. Approximately 6% of tumors detected as adrenal incidentalomas are adrenal cysts, as observed from the data of surgical series [2, 3]; however, a recent prospective study clarified that the incidence is much lower (< 1%) [4]. Adrenal cysts are classified as vascular or endothelial, epithelial, or parasitic [1, 5]. Pseudocysts are the most common type of adrenal cysts [6, 7]. Endothelial cysts associated with adrenal neoplasms are rare, with only a few reported cases [6, 8]. In addition, the cases of unilateral endothelial cysts and bilateral adrenal neoplasms have not been reported, to the best of our knowledge.
Primary aldosteronism is caused by the autonomous secretion of aldosterone owing to aldosterone-producing adenoma, multiple adrenocortical micronodules, and diffuse adrenocortical hyperplasia of the zona glomerulosa [9]. These conditions are known to be associated with high serum aldosterone and low renin levels, resulting in hypertension. However, we recently experienced a case of diffuse hyperplasia of the zona glomerulosa, positive for 18-hydroxylase: aldosterone synthase (CYP11β2), in which the patient had normal serum aldosterone levels, renin activity, and blood pressure.
Here, we report a rare case of bilateral adrenal adenomas with unilateral adrenal endothelial cysts. The possibility of sodium-glucose cotransporter protein 2 (SGLT2) inhibitor causing bilateral hyperplasia of the zona glomerulosa of the adrenal gland will also be discussed.
1. Case Presentation
A 65-year-old Japanese woman was referred to our hospital for characterization of the bilateral adrenal incidentaloma. At age 63, the patient was diagnosed with type 2 diabetes, which had been treated with diet and exercise therapy, and a gallstone identified by abdominal ultrasonography at a nearby clinic. Other than the diabetes and gallstone, she did not have any past medical history that needs specific mention. At age 64, the patient was administered an SGLT2 inhibitor, empagliflozin (10 mg/day), without any other medications and underwent abdominal ultrasonography for follow-up of the gallstone; however, adrenal masses were not identified at this point. At age 65, adrenal masses were incidentally identified during the abdominal ultrasonography during the follow-up examination of the gallstone. Consequently, subsequent plain abdominal computed tomography (CT) was performed, which revealed bilateral masses measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side (Fig. 1A). The right-sided mass was flat, with a small high-density spot, and heterogeneous, with a high-density (30-50 Hounsfield units [H]) and a low-density area (10-20 H). The left-sided mass was almost round with a relatively heterogeneous density (10-40 H).
Figure 1. Computed tomography (CT) scans of the right and left adrenal area. A, Plain CT showing a mass on the left and right sides (measuring 6.2 × 2.5 cm and 4.6 × 4.1 cm, respectively). B, Contrast-enhanced CT. C to F, Magnetic resonance imaging (MRI). C and D, T2-weighted images and images E, in phase and F, out of phase using chemical shift MRI.
The patient was admitted to our hospital for detailed examination. On admission, the patient did not present any signs or symptoms associated with excess adrenal cortical hormone levels or its deficiency. She had been taking an antidiabetic drug (empagliflozin, 10 mg/day) for approximately 1 year, and her diabetes was well controlled (fasting blood glucose: 116 mg/dL, glycated hemoglobin [hemoglobin A1c]: 6.9%). Between the third and first month prior to her introduction to our hospital, the patient used an ointment containing betamethasone butyrate propionate (exogenous glucocorticoid) for dermatitis. Physical examination revealed no significant findings. Clinical parameters were as follows: body height, 145.9 cm; body weight, 55.9 kg; blood pressure, 122/60 mm Hg; and heart rate, 60 beats/min. The laboratory data are presented in Table 1. The complete blood count and blood biochemistry tests were almost within the normal range.
Table 1. Laboratory findings of the patient
Peripheral blood Endocrinological data Load test
WBC 6060/mm3 (3300-8600) (Plasma) (CRH load)
RBC 462 × 104/mm3 (386-492) Epinephrine 24 pg/mL (0-100) ACTH 0 min 23.1 pg/mL
Hb 15.0 g/dL (11.6-14.8) Norepinephrine 304 pg/mL (100-450) 30 min 185.9 pg/mL
Ht 44.3% (35.1-44.4) Dopamine 10 pg/mL (0-20) 60 min 155.2 pg/mL
Plt 17.8 × 104/mm3 (15.8-34.8) Renin 2.3 ng/mL/h (0.3-5.4) 90 min 65.6 pg/mL
Aldosterone 149 pg/mL (29.9-159) 120 min 37.3 pg/mL
Biochemical data ARR 65 (< 200) Cortisol 0 min 4.5 μg/dL
T.P. 7.2 g/dL (6.6-8.1) ACTH (06:00) 32.0 pg/mL (7.2-63.3) 30 min 4.8 μg/dL
Albumin 4.2 g/dL (4.1-5.1) (12:00) 10.4 pg/mL 60 min 5.5 μg/dL
T.Bil 0.6 mg/dL (0.4-1.5) (18:00) 12.5 pg/mL 90 min 5.7 μg/dL
AST 25 U/L (13-30) (23:00) 13.6 pg/mL 120 min 5.5 μg/dL
ALT 29 U/L (7-23) Cortisol (06:00) 7.0 μg/dL (6.2-19.4)
LDH 248 U/L (124-222) (12:00) 4.4 μg/dL (ACTH load)
ALP 156 U/L (106-322) (18:00) 3.4 μg/dL Cortisol 0 min 4.3 μg/dL
rGTP 28 U/L (9-32) (23:00) 3.4 μg/dL 30 min 4.5 μg/dL
BUN 13 mg/dL (8-20) DHEA-S 96 μg/dL (12-133) 60 min 5.2 μg/dL
Crea 0.68 mg/dL (0.46-0.79) 90 min 5.7 μg/dL
Na 138 mEq/L (138-145) (Urine) 120 min 6.0 μg/dL
K 4.2 mEq/L (3.6-4.8) Epinephrine 8.2 μg/d (3.4-26.9)
Cl 105 mEq/L (101-108) Norepinephrine 133.3 μg/d (48.6-168.4)
Glucose 116 mg/dL (73-109) Dopamine 800.2 μg/d (365-961.5)
T.chol 177 mg/dL (142-220) Aldosterone 11 μg/d (0-10)
HbA1c 6.9% (4.9-6.2) Cortisol 75.3 μg/d (11.2-80.3)
sIL-2R 325 U/mL (121-613)
Reference ranges are in parentheses.
Abbreviations: ACTH, adrenocorticotropin; ALP, alkaline phosphatase; ALT, alanine transferase; ARR, aldosterone/renin ratio; AST, aspartate transaminase; BUN, blood urea nitrogen; Cl, chlorine; Crea, creatinine; DHEA-S, dehydroepiandrosterone-sulfate; Hb, hemoglobin; HbA1c, glycated hemoglobin; Ht, hematocrit; K, potassium; LDH, lactate dehydrogenase; Na, natrium; Plt, platelets; RBC, red blood cells; rGTP, γ-glutamyl transferase; sIL-2R, soluble interleukin-2 receptor; T.Bil, total bilirubin; T.chol, total cholesterol; T.P, total protein; WBC, white blood cells.
Endocrinological data are also presented in Table 1. Blood and 24-hour urine catecholamines were within the normal range. Plasma aldosterone concentration of 149 pg/mL, plasma renin activity of 2.3 ng/mL/h, and aldosterone/renin ratio of 65 were within the normal range. Urine aldosterone level (11 µg/day) was slightly elevated. Cortisol and adrenocorticotropin (ACTH) levels early in the morning were 5.3 µg/dL and 15.8 pg/mL (at an outpatient clinic) and 7.0 µg/dL and 32.0 pg/mL (after hospitalization), respectively (cortisol and ACTH levels were measured by Eclusys Cortisol II and Eclusys ACTH; reference values were 6.2-19.4 µg/dL and 7.2-63.3 pg/mL, respectively [Roche Diagnostics Inc]). In addition, the cortisol levels at 12:00, 18:00, and 23:00 h were 4.4, 3.4, and 3.4 µg/dL, respectively. Although adrenal insufficiency could be caused by prior exogenous corticosteroid use, load test with adrenocorticotropic hormone (ACTH: tetracosactide acetate 250 μg) was performed and the ACTH-stimulated cortisol response was low (cortisol less than 18 μg/dL as a basis for adrenal insufficiency). Load test with corticotropin-releasing hormone (CRH:corticorelin 100 μg) was also performed and the CRH-stimulated ACTH response was intact, but the cortisol response was low. These results indicated secondary adrenocortical hypofunction, probably due to the ointment containing glucocorticoid.
In addition to a plain CT, contrast-enhanced CT was also performed (Fig. 1B). The bilateral tumor showed a clear margin. Cystic regions were clearly detected in the right adrenal region. Magnetic resonance imaging (MRI) revealed some encapsulated fluid lesions in the right-sided mass with high signal intensity on T2-weighted images (Fig. 1C and 1D), suggesting the possibility of cysts or hemangiomas. The left-sided mass showed higher signal intensity than the liver on T2-weighted images. On chemical shift MRI (Fig. 1E and 1F) of the adrenal glands, the loss of signal intensity was not detected in out-of-phase imaging when compared with that of the spleen, suggesting the possibility of malignancy rather than adenoma [10]. However, on 18F-fluorodeoxyglucose positron emission tomography (PET), no suspicious malignant lesion was detected.
The patient underwent laparoscopic right adrenalectomy because the possibility of malignancy could not be excluded. The resected right adrenal gland weighed 45 g, and the tumor measured 45 × 40 × 32 mm. Representative histological findings are illustrated in Fig. 2A and 2B. The tumor was composed of compact cells with eosinophilic cytoplasm and scattered foci of clear cells. Based on the Weiss criteria, the tumor was diagnosed as an adrenocortical adenoma, and the cysts were detected adjacent to the tumor. Most of the right adrenal glands remained intact.
Figure 2. Photomicrograph of the resected tumors and adrenal glands (hematoxylin-eosin stain). A, Intact adrenal tissue (blue arrows) and tumor with a cyst in the right side. B, Enlarged view of the dotted region A. C, intact adrenal tissue (blue arrows) and tumor in the left side. D, Enlarged view of the dotted region C.
While the characteristics of the left adrenal lesion could not be determined, the left adrenal gland had a different shape from the right adrenal mass, and the possibility of malignancy could not be completely excluded. Therefore, the patient subsequently underwent laparoscopic left adrenalectomy. The resected left adrenal gland weighed 54 g, and the tumor measured 65 × 50 × 30 mm. Representative histological findings are illustrated in Fig. 2C and 2D. The histological features of the tumor in the left adrenal gland were similar to those in the right adrenal gland. The tumor on the left side was also diagnosed as an adrenocortical adenoma. No cysts were discernible in the left resected specimen, and most of the left adrenal glands remained intact.
In addition to the hematoxylin-eosin stain, we immunolocalized steroidogenic enzymes in both the resected adrenal glands (Figs. 3-5). In both tumors, immunoreactivity of 3β-hydroxysteroid dehydrogenase (HSD3β), 17α-hydroxylase, and 11β-hydroxylase (Fig. 3A and 3D) was diffusely detected but that of CYP11β2 [9, 11] was not (Fig. 3B and 3E). These results demonstrate that the tumor cells could produce cortisol but not aldosterone. Immunoreactivity of dehydroepiandrosterone-sulfotransferase (DHEA-ST) in the zona reticularis of the attached nonneoplastic adrenal cortex, which reflects the long-term dynamics of the hypothalamus-pituitary-adrenal (HPA) axis, was within normal limits (Fig. 3C and 3F). Therefore, cortisol produced by these tumors did not affect the HPA axis in the patient. Ki-67 labeling indices were 2.5% in the right adrenal tumor and less than 1% in the left adrenal tumor. The right-sided cysts were diagnosed as endothelial cysts because the monolayer lining cells were positive for CD31 immunoreactivity (Fig. 4). The nonneoplastic adrenal glands adjacent to the tumors on both sides had similar pathological features: morphologically hyperplastic in the zona glomerulosa (immunohistochemically positive for HSD3β and CYP11β2 [Fig. 3B and 3E and Fig. 5]) [9]. The final diagnosis of the resected adrenal glands following detailed analyses of steroidogenesis was that of a bilateral nonfunctional adrenocortical adenoma with cortisol-producing ability, with endothelial cyst formation and bilateral diffuse hyperplasia of the zona glomerulosa in the adjacent nonneoplastic adrenal glands.
Figure 3. Photomicrograph of the resected tumors and adrenal glands in A to C, the right side and D to F, the left side. A and D, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). The zona fasciculata and zona reticularis of the adrenal glands were positive for CYP11β1. Tumors were also positive for CYP11β1. B and E, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). Lined positivity for CYP11β2 of the zona glomerulosa was detected (blue arrows). Tumors were negative for CYP11β2. C and F, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST). The zona reticularis of the adrenal glands was positive for DHEA-ST. Tumors were negative for DHEA-ST.
Figure 4. Photomicrograph of the right-sided cystic region (immunohistochemical labeling for CD31). The monolayer lining cells of the cyst wall were CD31 positive, indicating endothelial cysts.
Figure 5. Photomicrograph of the resected intact adrenal tissue. Morphologically hyperplastic feature was detected in the zona glomerulosa. A, Hematoxylin-eosin staining. B, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). C, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). D, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST).
The postoperative course of the patient was uneventful. Hydrocortisone replacement was continued. Fludrocortisone was not administered according to a clinical practice guideline on primary adrenal insufficiency by the Japan Endocrine Society [12]. However, the clinical practice guideline of the Endocrine Society recommends mineral corticoid replacement with fludrocortisone and no restriction on salt intake [13]. Her blood pressure was 102 to 120/56 to 80 mm Hg. The patient’s blood biochemistry data were almost within the normal range. Fasting blood glucose and hemoglobin A1c levels were improved, reaching 100 mg/dL and 6.5%, respectively, without the administration of SGLT2 inhibitor or other diabetic medications (empagliflozin was stopped before the first surgery). This remission of diabetes might be caused by the reduction of body weight and cessation of the exogenous glucocorticoid.
2. Discussion
In our case, the adrenal glands showed relatively large bilateral adrenal incidentalomas (measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side) and unilateral cysts on the right side. In addition, these tumor masses showed a density of 30 to 50 H on the right side and 10 to 40 H on the left side on CT. To date, 24% of adrenal incidentalomas measuring more than 4 cm in diameter have been reported as being malignant lesions, with 90% of adrenal carcinomas having been reported to be larger than 4 cm in diameter [14]. The lipid content of the adrenal mass results in low attenuation on CT, which enables the distinction of adenomas from nonadenomas; adenomas have low attenuation (≤ 10 H) on CT [14]. Moreover, discerning the malignancy of the adrenal cystic lesions precisely, without histological diagnosis, is difficult [15]. Furthermore, the prevalence of benign adrenal cortical adenomas has been reported to increase with age [14]. In our case, surgical excision was based on the following conditions: surgical removal should be considered for nonfunctional adrenal masses measuring more than 4 cm unless there is a clear benign cause [16, 17] and should also be considered for masses measuring more than 4.6 cm or more than 20 H on CT [18]. In addition, because adrenal carcinomas could be associated with benign-appearing cysts, whole-specimen exploration of resected tissues is definitively recommended to rule out malignancy [19].
We performed multiple scans: CT, MRI, and PET. When an adrenal tumor has a large size and high attenuation as detected by CT scan, surgery without multiple scans was an appropriate option. If this case showed single laterality, we would proceed to surgery without multiple scans. However, this case manifested as a bilateral adrenal tumor. We tried to investigate the possibility of leaving the adrenal gland on the one side and begin with surgical resection of the other, but eventually surgery on both sides was needed. This is the reason for undertaking multiple scans and the separate adrenalectomies.
Approximately 15% of adrenal incidentalomas have been reported to be bilateral [14, 16]. In bilateral cases, adrenocortical hypofunction could occur owing to the damage of normal adrenal glands by tumor masses; therefore, screening of the adrenal glands’ function has been recommended [14, 16]. Adrenocortical hypofunction was observed in our case during the preoperative diagnosis. Based on low serum cortisol levels and the results of the ACTH and CRH load test, secondary but not primary adrenal insufficiency was suspected as being the cause of adrenocortical hypofunction. In fact, the postoperative histological study revealed almost intact adrenal glands and bilateral adenomas, with cortisol-producing potential, which did not influence the HPA axis because of normal histological features of the zona fasciculata and reticularis and intact expression of DHEA-ST in the zona reticularis. Therefore, the adrenal insufficiency in this case might have been caused by the temporary use of an exogeneous glucocorticoid and not by direct damage to the adrenal glands by bilateral tumors.
Adrenal endothelial cysts are rare diseases, and cases complicated with adrenal neoplasms are known to be extremely rare [6, 8], with a female predominance and a right-sided prevalence [7], as observed in our case. The pathogenesis of an endothelial cyst with an adrenocortical adenoma has been speculated by a previous study: local circulatory failure by repeated cycles of thrombus formation and recanalization and blood flow communication to a preexisting hemangioma [6].
In our case, in addition to bilateral adrenocortical adenoma with endothelial cysts, morphologically and immunohistochemically confirmed diffuse adrenal hyperplasia of the zona glomerulosa was detected. Although serum aldosterone levels, serum renin activity, and blood pressure were all within the normal range, detailed examination of the resected adrenal gland revealed diffuse hyperplasia of the zona glomerulosa, which was diffusely positive for CYP11β2. High sodium intake in the modern lifestyle has been reported to diminish the area of zona glomerulosa with aging [20, 21] as the renin-angiotensin-aldosterone system (RAAS) is relatively suppressed [20]. Consequently, elderly people usually have a smaller area of zona glomerulosa. Hyperplasia of the zona glomerulosa was detected during excessive activation of the RAAS, which further results in secondary aldosteronism [20]. The patient in our study did not have diseases causing secondary aldosteronism, but one possibility for the activated RAAS was the use of empagliflozin, an SGLT2 inhibitor, which led to diffuse hyperplasia of the zona glomerulosa. Serum renin and aldosterone levels have been reported to increase significantly with SGLT2 inhibitor use within 1 month, which is associated with a decrease in extracellular fluid [22, 23]. Inconsistent results have been reported for the changes in RAAS in long-term treatments with SGLT2 inhibitors [24]. Although renin activity and aldosterone levels both were reported to normalize after 6 months of SGLT2 inhibitor treatment in some studies [22], increased RAAS activation after 24 weeks of SGLT2 inhibitor treatment was reported in another study [25]. Dehydration is one of the most frequent adverse events of SGLT2 inhibitor use [26, 27] due to the excretion of abundant urinary glucose. In our case, although serum renin and aldosterone levels were within the normal range, urine aldosterone level was above normal, and serum aldosterone level was close to the upper limit of the normal range. In addition, our patient had increased blood hemoglobin and hematocrit levels (15.0-15.7g/dL and 43.5%-46.4%, respectively), which suggest dehydration associated with SGLT2 inhibitor treatment before the operation, which returned to normal levels (13.9-14.5g/dL and 40.5%-42.6%, respectively) after discontinuation of the SGLT2 inhibitor post operation. In our study, surgical resection of the bilateral adrenal glands for the treatment of an adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine the morphology and histology of adrenal glands under SGLT2 inhibitor treatment, leading to unexpected findings of diffuse bilateral hyperplasia of the zona glomerulosa, with no functional changes in renin and aldosterone levels, and no increase in blood pressure. These results suggest the possibility of SGLT2 inhibitors having some effect on the zona glomerulosa of the adrenal gland; for instance, the latent loss of plasma volume caused by the SGLT2 inhibitor stimulating the zona glomerulosa chronically, leading to hyperplasia.
3. Conclusion
To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts coexisted, demonstrating the complexity and difficulty of preoperative diagnosis of bilateral adrenal incidentaloma. The adrenal mass in our case was not malignant, but a large tumor with cysts should be considered for resection because potential malignancy is ruled out by detailed histopathological evaluation of the lesions. In addition, surgical resection of bilateral adrenal glands for the treatment of adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine in detail the morphology and histology of the adrenal glands under SGLT2 inhibitor treatment, leading to an unexpected finding of diffuse bilateral hyperplasia of the zona glomerulosa in nonneoplastic adrenal glands, without clinically demonstrating primary aldosteronism. Therefore, we advocate a new hypothesis that SGLT2 inhibitors affect the zona glomerulosa of the adrenal gland; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of zona glomerulosa based on the data in this singular case. Because this can be confirmed only under limited conditions, additional case reports or animal model studies on adrenal gland histology under SGLT2 inhibition are warranted.
Acknowledgments
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Abbreviations
ACTH adrenocorticotropic hormone
CRH corticotropin-releasing hormone
CT computed tomography
CYP11β2 18-hydroxylase
DHEA-ST dehydroepiandrosterone-sulfotransferase
HPA hypothalamus-pituitary-adrenal
HSD3β 3β-hydroxysteroid dehydrogenase
H Hounsfield unit
MRI magnetic resonance imaging
PET positron emission tomography
RAAS renin-angiotensin-aldosterone system
SGLT2 sodium-glucose co-transport protein-2
Additional Information
Disclosure Summary: The authors have no conflicts of interest to report.
Data Availability
Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study. | Recovering | ReactionOutcome | CC BY-NC-ND | 33381672 | 19,439,388 | 2021-02-01 |
What was the outcome of reaction 'Adrenal neoplasm'? | A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.
Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.
Adrenal cysts are rare cystic masses that are detected incidentally during autopsy in 0.06% of the population [1]. Approximately 6% of tumors detected as adrenal incidentalomas are adrenal cysts, as observed from the data of surgical series [2, 3]; however, a recent prospective study clarified that the incidence is much lower (< 1%) [4]. Adrenal cysts are classified as vascular or endothelial, epithelial, or parasitic [1, 5]. Pseudocysts are the most common type of adrenal cysts [6, 7]. Endothelial cysts associated with adrenal neoplasms are rare, with only a few reported cases [6, 8]. In addition, the cases of unilateral endothelial cysts and bilateral adrenal neoplasms have not been reported, to the best of our knowledge.
Primary aldosteronism is caused by the autonomous secretion of aldosterone owing to aldosterone-producing adenoma, multiple adrenocortical micronodules, and diffuse adrenocortical hyperplasia of the zona glomerulosa [9]. These conditions are known to be associated with high serum aldosterone and low renin levels, resulting in hypertension. However, we recently experienced a case of diffuse hyperplasia of the zona glomerulosa, positive for 18-hydroxylase: aldosterone synthase (CYP11β2), in which the patient had normal serum aldosterone levels, renin activity, and blood pressure.
Here, we report a rare case of bilateral adrenal adenomas with unilateral adrenal endothelial cysts. The possibility of sodium-glucose cotransporter protein 2 (SGLT2) inhibitor causing bilateral hyperplasia of the zona glomerulosa of the adrenal gland will also be discussed.
1. Case Presentation
A 65-year-old Japanese woman was referred to our hospital for characterization of the bilateral adrenal incidentaloma. At age 63, the patient was diagnosed with type 2 diabetes, which had been treated with diet and exercise therapy, and a gallstone identified by abdominal ultrasonography at a nearby clinic. Other than the diabetes and gallstone, she did not have any past medical history that needs specific mention. At age 64, the patient was administered an SGLT2 inhibitor, empagliflozin (10 mg/day), without any other medications and underwent abdominal ultrasonography for follow-up of the gallstone; however, adrenal masses were not identified at this point. At age 65, adrenal masses were incidentally identified during the abdominal ultrasonography during the follow-up examination of the gallstone. Consequently, subsequent plain abdominal computed tomography (CT) was performed, which revealed bilateral masses measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side (Fig. 1A). The right-sided mass was flat, with a small high-density spot, and heterogeneous, with a high-density (30-50 Hounsfield units [H]) and a low-density area (10-20 H). The left-sided mass was almost round with a relatively heterogeneous density (10-40 H).
Figure 1. Computed tomography (CT) scans of the right and left adrenal area. A, Plain CT showing a mass on the left and right sides (measuring 6.2 × 2.5 cm and 4.6 × 4.1 cm, respectively). B, Contrast-enhanced CT. C to F, Magnetic resonance imaging (MRI). C and D, T2-weighted images and images E, in phase and F, out of phase using chemical shift MRI.
The patient was admitted to our hospital for detailed examination. On admission, the patient did not present any signs or symptoms associated with excess adrenal cortical hormone levels or its deficiency. She had been taking an antidiabetic drug (empagliflozin, 10 mg/day) for approximately 1 year, and her diabetes was well controlled (fasting blood glucose: 116 mg/dL, glycated hemoglobin [hemoglobin A1c]: 6.9%). Between the third and first month prior to her introduction to our hospital, the patient used an ointment containing betamethasone butyrate propionate (exogenous glucocorticoid) for dermatitis. Physical examination revealed no significant findings. Clinical parameters were as follows: body height, 145.9 cm; body weight, 55.9 kg; blood pressure, 122/60 mm Hg; and heart rate, 60 beats/min. The laboratory data are presented in Table 1. The complete blood count and blood biochemistry tests were almost within the normal range.
Table 1. Laboratory findings of the patient
Peripheral blood Endocrinological data Load test
WBC 6060/mm3 (3300-8600) (Plasma) (CRH load)
RBC 462 × 104/mm3 (386-492) Epinephrine 24 pg/mL (0-100) ACTH 0 min 23.1 pg/mL
Hb 15.0 g/dL (11.6-14.8) Norepinephrine 304 pg/mL (100-450) 30 min 185.9 pg/mL
Ht 44.3% (35.1-44.4) Dopamine 10 pg/mL (0-20) 60 min 155.2 pg/mL
Plt 17.8 × 104/mm3 (15.8-34.8) Renin 2.3 ng/mL/h (0.3-5.4) 90 min 65.6 pg/mL
Aldosterone 149 pg/mL (29.9-159) 120 min 37.3 pg/mL
Biochemical data ARR 65 (< 200) Cortisol 0 min 4.5 μg/dL
T.P. 7.2 g/dL (6.6-8.1) ACTH (06:00) 32.0 pg/mL (7.2-63.3) 30 min 4.8 μg/dL
Albumin 4.2 g/dL (4.1-5.1) (12:00) 10.4 pg/mL 60 min 5.5 μg/dL
T.Bil 0.6 mg/dL (0.4-1.5) (18:00) 12.5 pg/mL 90 min 5.7 μg/dL
AST 25 U/L (13-30) (23:00) 13.6 pg/mL 120 min 5.5 μg/dL
ALT 29 U/L (7-23) Cortisol (06:00) 7.0 μg/dL (6.2-19.4)
LDH 248 U/L (124-222) (12:00) 4.4 μg/dL (ACTH load)
ALP 156 U/L (106-322) (18:00) 3.4 μg/dL Cortisol 0 min 4.3 μg/dL
rGTP 28 U/L (9-32) (23:00) 3.4 μg/dL 30 min 4.5 μg/dL
BUN 13 mg/dL (8-20) DHEA-S 96 μg/dL (12-133) 60 min 5.2 μg/dL
Crea 0.68 mg/dL (0.46-0.79) 90 min 5.7 μg/dL
Na 138 mEq/L (138-145) (Urine) 120 min 6.0 μg/dL
K 4.2 mEq/L (3.6-4.8) Epinephrine 8.2 μg/d (3.4-26.9)
Cl 105 mEq/L (101-108) Norepinephrine 133.3 μg/d (48.6-168.4)
Glucose 116 mg/dL (73-109) Dopamine 800.2 μg/d (365-961.5)
T.chol 177 mg/dL (142-220) Aldosterone 11 μg/d (0-10)
HbA1c 6.9% (4.9-6.2) Cortisol 75.3 μg/d (11.2-80.3)
sIL-2R 325 U/mL (121-613)
Reference ranges are in parentheses.
Abbreviations: ACTH, adrenocorticotropin; ALP, alkaline phosphatase; ALT, alanine transferase; ARR, aldosterone/renin ratio; AST, aspartate transaminase; BUN, blood urea nitrogen; Cl, chlorine; Crea, creatinine; DHEA-S, dehydroepiandrosterone-sulfate; Hb, hemoglobin; HbA1c, glycated hemoglobin; Ht, hematocrit; K, potassium; LDH, lactate dehydrogenase; Na, natrium; Plt, platelets; RBC, red blood cells; rGTP, γ-glutamyl transferase; sIL-2R, soluble interleukin-2 receptor; T.Bil, total bilirubin; T.chol, total cholesterol; T.P, total protein; WBC, white blood cells.
Endocrinological data are also presented in Table 1. Blood and 24-hour urine catecholamines were within the normal range. Plasma aldosterone concentration of 149 pg/mL, plasma renin activity of 2.3 ng/mL/h, and aldosterone/renin ratio of 65 were within the normal range. Urine aldosterone level (11 µg/day) was slightly elevated. Cortisol and adrenocorticotropin (ACTH) levels early in the morning were 5.3 µg/dL and 15.8 pg/mL (at an outpatient clinic) and 7.0 µg/dL and 32.0 pg/mL (after hospitalization), respectively (cortisol and ACTH levels were measured by Eclusys Cortisol II and Eclusys ACTH; reference values were 6.2-19.4 µg/dL and 7.2-63.3 pg/mL, respectively [Roche Diagnostics Inc]). In addition, the cortisol levels at 12:00, 18:00, and 23:00 h were 4.4, 3.4, and 3.4 µg/dL, respectively. Although adrenal insufficiency could be caused by prior exogenous corticosteroid use, load test with adrenocorticotropic hormone (ACTH: tetracosactide acetate 250 μg) was performed and the ACTH-stimulated cortisol response was low (cortisol less than 18 μg/dL as a basis for adrenal insufficiency). Load test with corticotropin-releasing hormone (CRH:corticorelin 100 μg) was also performed and the CRH-stimulated ACTH response was intact, but the cortisol response was low. These results indicated secondary adrenocortical hypofunction, probably due to the ointment containing glucocorticoid.
In addition to a plain CT, contrast-enhanced CT was also performed (Fig. 1B). The bilateral tumor showed a clear margin. Cystic regions were clearly detected in the right adrenal region. Magnetic resonance imaging (MRI) revealed some encapsulated fluid lesions in the right-sided mass with high signal intensity on T2-weighted images (Fig. 1C and 1D), suggesting the possibility of cysts or hemangiomas. The left-sided mass showed higher signal intensity than the liver on T2-weighted images. On chemical shift MRI (Fig. 1E and 1F) of the adrenal glands, the loss of signal intensity was not detected in out-of-phase imaging when compared with that of the spleen, suggesting the possibility of malignancy rather than adenoma [10]. However, on 18F-fluorodeoxyglucose positron emission tomography (PET), no suspicious malignant lesion was detected.
The patient underwent laparoscopic right adrenalectomy because the possibility of malignancy could not be excluded. The resected right adrenal gland weighed 45 g, and the tumor measured 45 × 40 × 32 mm. Representative histological findings are illustrated in Fig. 2A and 2B. The tumor was composed of compact cells with eosinophilic cytoplasm and scattered foci of clear cells. Based on the Weiss criteria, the tumor was diagnosed as an adrenocortical adenoma, and the cysts were detected adjacent to the tumor. Most of the right adrenal glands remained intact.
Figure 2. Photomicrograph of the resected tumors and adrenal glands (hematoxylin-eosin stain). A, Intact adrenal tissue (blue arrows) and tumor with a cyst in the right side. B, Enlarged view of the dotted region A. C, intact adrenal tissue (blue arrows) and tumor in the left side. D, Enlarged view of the dotted region C.
While the characteristics of the left adrenal lesion could not be determined, the left adrenal gland had a different shape from the right adrenal mass, and the possibility of malignancy could not be completely excluded. Therefore, the patient subsequently underwent laparoscopic left adrenalectomy. The resected left adrenal gland weighed 54 g, and the tumor measured 65 × 50 × 30 mm. Representative histological findings are illustrated in Fig. 2C and 2D. The histological features of the tumor in the left adrenal gland were similar to those in the right adrenal gland. The tumor on the left side was also diagnosed as an adrenocortical adenoma. No cysts were discernible in the left resected specimen, and most of the left adrenal glands remained intact.
In addition to the hematoxylin-eosin stain, we immunolocalized steroidogenic enzymes in both the resected adrenal glands (Figs. 3-5). In both tumors, immunoreactivity of 3β-hydroxysteroid dehydrogenase (HSD3β), 17α-hydroxylase, and 11β-hydroxylase (Fig. 3A and 3D) was diffusely detected but that of CYP11β2 [9, 11] was not (Fig. 3B and 3E). These results demonstrate that the tumor cells could produce cortisol but not aldosterone. Immunoreactivity of dehydroepiandrosterone-sulfotransferase (DHEA-ST) in the zona reticularis of the attached nonneoplastic adrenal cortex, which reflects the long-term dynamics of the hypothalamus-pituitary-adrenal (HPA) axis, was within normal limits (Fig. 3C and 3F). Therefore, cortisol produced by these tumors did not affect the HPA axis in the patient. Ki-67 labeling indices were 2.5% in the right adrenal tumor and less than 1% in the left adrenal tumor. The right-sided cysts were diagnosed as endothelial cysts because the monolayer lining cells were positive for CD31 immunoreactivity (Fig. 4). The nonneoplastic adrenal glands adjacent to the tumors on both sides had similar pathological features: morphologically hyperplastic in the zona glomerulosa (immunohistochemically positive for HSD3β and CYP11β2 [Fig. 3B and 3E and Fig. 5]) [9]. The final diagnosis of the resected adrenal glands following detailed analyses of steroidogenesis was that of a bilateral nonfunctional adrenocortical adenoma with cortisol-producing ability, with endothelial cyst formation and bilateral diffuse hyperplasia of the zona glomerulosa in the adjacent nonneoplastic adrenal glands.
Figure 3. Photomicrograph of the resected tumors and adrenal glands in A to C, the right side and D to F, the left side. A and D, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). The zona fasciculata and zona reticularis of the adrenal glands were positive for CYP11β1. Tumors were also positive for CYP11β1. B and E, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). Lined positivity for CYP11β2 of the zona glomerulosa was detected (blue arrows). Tumors were negative for CYP11β2. C and F, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST). The zona reticularis of the adrenal glands was positive for DHEA-ST. Tumors were negative for DHEA-ST.
Figure 4. Photomicrograph of the right-sided cystic region (immunohistochemical labeling for CD31). The monolayer lining cells of the cyst wall were CD31 positive, indicating endothelial cysts.
Figure 5. Photomicrograph of the resected intact adrenal tissue. Morphologically hyperplastic feature was detected in the zona glomerulosa. A, Hematoxylin-eosin staining. B, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). C, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). D, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST).
The postoperative course of the patient was uneventful. Hydrocortisone replacement was continued. Fludrocortisone was not administered according to a clinical practice guideline on primary adrenal insufficiency by the Japan Endocrine Society [12]. However, the clinical practice guideline of the Endocrine Society recommends mineral corticoid replacement with fludrocortisone and no restriction on salt intake [13]. Her blood pressure was 102 to 120/56 to 80 mm Hg. The patient’s blood biochemistry data were almost within the normal range. Fasting blood glucose and hemoglobin A1c levels were improved, reaching 100 mg/dL and 6.5%, respectively, without the administration of SGLT2 inhibitor or other diabetic medications (empagliflozin was stopped before the first surgery). This remission of diabetes might be caused by the reduction of body weight and cessation of the exogenous glucocorticoid.
2. Discussion
In our case, the adrenal glands showed relatively large bilateral adrenal incidentalomas (measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side) and unilateral cysts on the right side. In addition, these tumor masses showed a density of 30 to 50 H on the right side and 10 to 40 H on the left side on CT. To date, 24% of adrenal incidentalomas measuring more than 4 cm in diameter have been reported as being malignant lesions, with 90% of adrenal carcinomas having been reported to be larger than 4 cm in diameter [14]. The lipid content of the adrenal mass results in low attenuation on CT, which enables the distinction of adenomas from nonadenomas; adenomas have low attenuation (≤ 10 H) on CT [14]. Moreover, discerning the malignancy of the adrenal cystic lesions precisely, without histological diagnosis, is difficult [15]. Furthermore, the prevalence of benign adrenal cortical adenomas has been reported to increase with age [14]. In our case, surgical excision was based on the following conditions: surgical removal should be considered for nonfunctional adrenal masses measuring more than 4 cm unless there is a clear benign cause [16, 17] and should also be considered for masses measuring more than 4.6 cm or more than 20 H on CT [18]. In addition, because adrenal carcinomas could be associated with benign-appearing cysts, whole-specimen exploration of resected tissues is definitively recommended to rule out malignancy [19].
We performed multiple scans: CT, MRI, and PET. When an adrenal tumor has a large size and high attenuation as detected by CT scan, surgery without multiple scans was an appropriate option. If this case showed single laterality, we would proceed to surgery without multiple scans. However, this case manifested as a bilateral adrenal tumor. We tried to investigate the possibility of leaving the adrenal gland on the one side and begin with surgical resection of the other, but eventually surgery on both sides was needed. This is the reason for undertaking multiple scans and the separate adrenalectomies.
Approximately 15% of adrenal incidentalomas have been reported to be bilateral [14, 16]. In bilateral cases, adrenocortical hypofunction could occur owing to the damage of normal adrenal glands by tumor masses; therefore, screening of the adrenal glands’ function has been recommended [14, 16]. Adrenocortical hypofunction was observed in our case during the preoperative diagnosis. Based on low serum cortisol levels and the results of the ACTH and CRH load test, secondary but not primary adrenal insufficiency was suspected as being the cause of adrenocortical hypofunction. In fact, the postoperative histological study revealed almost intact adrenal glands and bilateral adenomas, with cortisol-producing potential, which did not influence the HPA axis because of normal histological features of the zona fasciculata and reticularis and intact expression of DHEA-ST in the zona reticularis. Therefore, the adrenal insufficiency in this case might have been caused by the temporary use of an exogeneous glucocorticoid and not by direct damage to the adrenal glands by bilateral tumors.
Adrenal endothelial cysts are rare diseases, and cases complicated with adrenal neoplasms are known to be extremely rare [6, 8], with a female predominance and a right-sided prevalence [7], as observed in our case. The pathogenesis of an endothelial cyst with an adrenocortical adenoma has been speculated by a previous study: local circulatory failure by repeated cycles of thrombus formation and recanalization and blood flow communication to a preexisting hemangioma [6].
In our case, in addition to bilateral adrenocortical adenoma with endothelial cysts, morphologically and immunohistochemically confirmed diffuse adrenal hyperplasia of the zona glomerulosa was detected. Although serum aldosterone levels, serum renin activity, and blood pressure were all within the normal range, detailed examination of the resected adrenal gland revealed diffuse hyperplasia of the zona glomerulosa, which was diffusely positive for CYP11β2. High sodium intake in the modern lifestyle has been reported to diminish the area of zona glomerulosa with aging [20, 21] as the renin-angiotensin-aldosterone system (RAAS) is relatively suppressed [20]. Consequently, elderly people usually have a smaller area of zona glomerulosa. Hyperplasia of the zona glomerulosa was detected during excessive activation of the RAAS, which further results in secondary aldosteronism [20]. The patient in our study did not have diseases causing secondary aldosteronism, but one possibility for the activated RAAS was the use of empagliflozin, an SGLT2 inhibitor, which led to diffuse hyperplasia of the zona glomerulosa. Serum renin and aldosterone levels have been reported to increase significantly with SGLT2 inhibitor use within 1 month, which is associated with a decrease in extracellular fluid [22, 23]. Inconsistent results have been reported for the changes in RAAS in long-term treatments with SGLT2 inhibitors [24]. Although renin activity and aldosterone levels both were reported to normalize after 6 months of SGLT2 inhibitor treatment in some studies [22], increased RAAS activation after 24 weeks of SGLT2 inhibitor treatment was reported in another study [25]. Dehydration is one of the most frequent adverse events of SGLT2 inhibitor use [26, 27] due to the excretion of abundant urinary glucose. In our case, although serum renin and aldosterone levels were within the normal range, urine aldosterone level was above normal, and serum aldosterone level was close to the upper limit of the normal range. In addition, our patient had increased blood hemoglobin and hematocrit levels (15.0-15.7g/dL and 43.5%-46.4%, respectively), which suggest dehydration associated with SGLT2 inhibitor treatment before the operation, which returned to normal levels (13.9-14.5g/dL and 40.5%-42.6%, respectively) after discontinuation of the SGLT2 inhibitor post operation. In our study, surgical resection of the bilateral adrenal glands for the treatment of an adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine the morphology and histology of adrenal glands under SGLT2 inhibitor treatment, leading to unexpected findings of diffuse bilateral hyperplasia of the zona glomerulosa, with no functional changes in renin and aldosterone levels, and no increase in blood pressure. These results suggest the possibility of SGLT2 inhibitors having some effect on the zona glomerulosa of the adrenal gland; for instance, the latent loss of plasma volume caused by the SGLT2 inhibitor stimulating the zona glomerulosa chronically, leading to hyperplasia.
3. Conclusion
To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts coexisted, demonstrating the complexity and difficulty of preoperative diagnosis of bilateral adrenal incidentaloma. The adrenal mass in our case was not malignant, but a large tumor with cysts should be considered for resection because potential malignancy is ruled out by detailed histopathological evaluation of the lesions. In addition, surgical resection of bilateral adrenal glands for the treatment of adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine in detail the morphology and histology of the adrenal glands under SGLT2 inhibitor treatment, leading to an unexpected finding of diffuse bilateral hyperplasia of the zona glomerulosa in nonneoplastic adrenal glands, without clinically demonstrating primary aldosteronism. Therefore, we advocate a new hypothesis that SGLT2 inhibitors affect the zona glomerulosa of the adrenal gland; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of zona glomerulosa based on the data in this singular case. Because this can be confirmed only under limited conditions, additional case reports or animal model studies on adrenal gland histology under SGLT2 inhibition are warranted.
Acknowledgments
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Abbreviations
ACTH adrenocorticotropic hormone
CRH corticotropin-releasing hormone
CT computed tomography
CYP11β2 18-hydroxylase
DHEA-ST dehydroepiandrosterone-sulfotransferase
HPA hypothalamus-pituitary-adrenal
HSD3β 3β-hydroxysteroid dehydrogenase
H Hounsfield unit
MRI magnetic resonance imaging
PET positron emission tomography
RAAS renin-angiotensin-aldosterone system
SGLT2 sodium-glucose co-transport protein-2
Additional Information
Disclosure Summary: The authors have no conflicts of interest to report.
Data Availability
Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study. | Recovering | ReactionOutcome | CC BY-NC-ND | 33381672 | 19,439,388 | 2021-02-01 |
What was the outcome of reaction 'Hyperplasia adrenal'? | A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.
Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.
Adrenal cysts are rare cystic masses that are detected incidentally during autopsy in 0.06% of the population [1]. Approximately 6% of tumors detected as adrenal incidentalomas are adrenal cysts, as observed from the data of surgical series [2, 3]; however, a recent prospective study clarified that the incidence is much lower (< 1%) [4]. Adrenal cysts are classified as vascular or endothelial, epithelial, or parasitic [1, 5]. Pseudocysts are the most common type of adrenal cysts [6, 7]. Endothelial cysts associated with adrenal neoplasms are rare, with only a few reported cases [6, 8]. In addition, the cases of unilateral endothelial cysts and bilateral adrenal neoplasms have not been reported, to the best of our knowledge.
Primary aldosteronism is caused by the autonomous secretion of aldosterone owing to aldosterone-producing adenoma, multiple adrenocortical micronodules, and diffuse adrenocortical hyperplasia of the zona glomerulosa [9]. These conditions are known to be associated with high serum aldosterone and low renin levels, resulting in hypertension. However, we recently experienced a case of diffuse hyperplasia of the zona glomerulosa, positive for 18-hydroxylase: aldosterone synthase (CYP11β2), in which the patient had normal serum aldosterone levels, renin activity, and blood pressure.
Here, we report a rare case of bilateral adrenal adenomas with unilateral adrenal endothelial cysts. The possibility of sodium-glucose cotransporter protein 2 (SGLT2) inhibitor causing bilateral hyperplasia of the zona glomerulosa of the adrenal gland will also be discussed.
1. Case Presentation
A 65-year-old Japanese woman was referred to our hospital for characterization of the bilateral adrenal incidentaloma. At age 63, the patient was diagnosed with type 2 diabetes, which had been treated with diet and exercise therapy, and a gallstone identified by abdominal ultrasonography at a nearby clinic. Other than the diabetes and gallstone, she did not have any past medical history that needs specific mention. At age 64, the patient was administered an SGLT2 inhibitor, empagliflozin (10 mg/day), without any other medications and underwent abdominal ultrasonography for follow-up of the gallstone; however, adrenal masses were not identified at this point. At age 65, adrenal masses were incidentally identified during the abdominal ultrasonography during the follow-up examination of the gallstone. Consequently, subsequent plain abdominal computed tomography (CT) was performed, which revealed bilateral masses measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side (Fig. 1A). The right-sided mass was flat, with a small high-density spot, and heterogeneous, with a high-density (30-50 Hounsfield units [H]) and a low-density area (10-20 H). The left-sided mass was almost round with a relatively heterogeneous density (10-40 H).
Figure 1. Computed tomography (CT) scans of the right and left adrenal area. A, Plain CT showing a mass on the left and right sides (measuring 6.2 × 2.5 cm and 4.6 × 4.1 cm, respectively). B, Contrast-enhanced CT. C to F, Magnetic resonance imaging (MRI). C and D, T2-weighted images and images E, in phase and F, out of phase using chemical shift MRI.
The patient was admitted to our hospital for detailed examination. On admission, the patient did not present any signs or symptoms associated with excess adrenal cortical hormone levels or its deficiency. She had been taking an antidiabetic drug (empagliflozin, 10 mg/day) for approximately 1 year, and her diabetes was well controlled (fasting blood glucose: 116 mg/dL, glycated hemoglobin [hemoglobin A1c]: 6.9%). Between the third and first month prior to her introduction to our hospital, the patient used an ointment containing betamethasone butyrate propionate (exogenous glucocorticoid) for dermatitis. Physical examination revealed no significant findings. Clinical parameters were as follows: body height, 145.9 cm; body weight, 55.9 kg; blood pressure, 122/60 mm Hg; and heart rate, 60 beats/min. The laboratory data are presented in Table 1. The complete blood count and blood biochemistry tests were almost within the normal range.
Table 1. Laboratory findings of the patient
Peripheral blood Endocrinological data Load test
WBC 6060/mm3 (3300-8600) (Plasma) (CRH load)
RBC 462 × 104/mm3 (386-492) Epinephrine 24 pg/mL (0-100) ACTH 0 min 23.1 pg/mL
Hb 15.0 g/dL (11.6-14.8) Norepinephrine 304 pg/mL (100-450) 30 min 185.9 pg/mL
Ht 44.3% (35.1-44.4) Dopamine 10 pg/mL (0-20) 60 min 155.2 pg/mL
Plt 17.8 × 104/mm3 (15.8-34.8) Renin 2.3 ng/mL/h (0.3-5.4) 90 min 65.6 pg/mL
Aldosterone 149 pg/mL (29.9-159) 120 min 37.3 pg/mL
Biochemical data ARR 65 (< 200) Cortisol 0 min 4.5 μg/dL
T.P. 7.2 g/dL (6.6-8.1) ACTH (06:00) 32.0 pg/mL (7.2-63.3) 30 min 4.8 μg/dL
Albumin 4.2 g/dL (4.1-5.1) (12:00) 10.4 pg/mL 60 min 5.5 μg/dL
T.Bil 0.6 mg/dL (0.4-1.5) (18:00) 12.5 pg/mL 90 min 5.7 μg/dL
AST 25 U/L (13-30) (23:00) 13.6 pg/mL 120 min 5.5 μg/dL
ALT 29 U/L (7-23) Cortisol (06:00) 7.0 μg/dL (6.2-19.4)
LDH 248 U/L (124-222) (12:00) 4.4 μg/dL (ACTH load)
ALP 156 U/L (106-322) (18:00) 3.4 μg/dL Cortisol 0 min 4.3 μg/dL
rGTP 28 U/L (9-32) (23:00) 3.4 μg/dL 30 min 4.5 μg/dL
BUN 13 mg/dL (8-20) DHEA-S 96 μg/dL (12-133) 60 min 5.2 μg/dL
Crea 0.68 mg/dL (0.46-0.79) 90 min 5.7 μg/dL
Na 138 mEq/L (138-145) (Urine) 120 min 6.0 μg/dL
K 4.2 mEq/L (3.6-4.8) Epinephrine 8.2 μg/d (3.4-26.9)
Cl 105 mEq/L (101-108) Norepinephrine 133.3 μg/d (48.6-168.4)
Glucose 116 mg/dL (73-109) Dopamine 800.2 μg/d (365-961.5)
T.chol 177 mg/dL (142-220) Aldosterone 11 μg/d (0-10)
HbA1c 6.9% (4.9-6.2) Cortisol 75.3 μg/d (11.2-80.3)
sIL-2R 325 U/mL (121-613)
Reference ranges are in parentheses.
Abbreviations: ACTH, adrenocorticotropin; ALP, alkaline phosphatase; ALT, alanine transferase; ARR, aldosterone/renin ratio; AST, aspartate transaminase; BUN, blood urea nitrogen; Cl, chlorine; Crea, creatinine; DHEA-S, dehydroepiandrosterone-sulfate; Hb, hemoglobin; HbA1c, glycated hemoglobin; Ht, hematocrit; K, potassium; LDH, lactate dehydrogenase; Na, natrium; Plt, platelets; RBC, red blood cells; rGTP, γ-glutamyl transferase; sIL-2R, soluble interleukin-2 receptor; T.Bil, total bilirubin; T.chol, total cholesterol; T.P, total protein; WBC, white blood cells.
Endocrinological data are also presented in Table 1. Blood and 24-hour urine catecholamines were within the normal range. Plasma aldosterone concentration of 149 pg/mL, plasma renin activity of 2.3 ng/mL/h, and aldosterone/renin ratio of 65 were within the normal range. Urine aldosterone level (11 µg/day) was slightly elevated. Cortisol and adrenocorticotropin (ACTH) levels early in the morning were 5.3 µg/dL and 15.8 pg/mL (at an outpatient clinic) and 7.0 µg/dL and 32.0 pg/mL (after hospitalization), respectively (cortisol and ACTH levels were measured by Eclusys Cortisol II and Eclusys ACTH; reference values were 6.2-19.4 µg/dL and 7.2-63.3 pg/mL, respectively [Roche Diagnostics Inc]). In addition, the cortisol levels at 12:00, 18:00, and 23:00 h were 4.4, 3.4, and 3.4 µg/dL, respectively. Although adrenal insufficiency could be caused by prior exogenous corticosteroid use, load test with adrenocorticotropic hormone (ACTH: tetracosactide acetate 250 μg) was performed and the ACTH-stimulated cortisol response was low (cortisol less than 18 μg/dL as a basis for adrenal insufficiency). Load test with corticotropin-releasing hormone (CRH:corticorelin 100 μg) was also performed and the CRH-stimulated ACTH response was intact, but the cortisol response was low. These results indicated secondary adrenocortical hypofunction, probably due to the ointment containing glucocorticoid.
In addition to a plain CT, contrast-enhanced CT was also performed (Fig. 1B). The bilateral tumor showed a clear margin. Cystic regions were clearly detected in the right adrenal region. Magnetic resonance imaging (MRI) revealed some encapsulated fluid lesions in the right-sided mass with high signal intensity on T2-weighted images (Fig. 1C and 1D), suggesting the possibility of cysts or hemangiomas. The left-sided mass showed higher signal intensity than the liver on T2-weighted images. On chemical shift MRI (Fig. 1E and 1F) of the adrenal glands, the loss of signal intensity was not detected in out-of-phase imaging when compared with that of the spleen, suggesting the possibility of malignancy rather than adenoma [10]. However, on 18F-fluorodeoxyglucose positron emission tomography (PET), no suspicious malignant lesion was detected.
The patient underwent laparoscopic right adrenalectomy because the possibility of malignancy could not be excluded. The resected right adrenal gland weighed 45 g, and the tumor measured 45 × 40 × 32 mm. Representative histological findings are illustrated in Fig. 2A and 2B. The tumor was composed of compact cells with eosinophilic cytoplasm and scattered foci of clear cells. Based on the Weiss criteria, the tumor was diagnosed as an adrenocortical adenoma, and the cysts were detected adjacent to the tumor. Most of the right adrenal glands remained intact.
Figure 2. Photomicrograph of the resected tumors and adrenal glands (hematoxylin-eosin stain). A, Intact adrenal tissue (blue arrows) and tumor with a cyst in the right side. B, Enlarged view of the dotted region A. C, intact adrenal tissue (blue arrows) and tumor in the left side. D, Enlarged view of the dotted region C.
While the characteristics of the left adrenal lesion could not be determined, the left adrenal gland had a different shape from the right adrenal mass, and the possibility of malignancy could not be completely excluded. Therefore, the patient subsequently underwent laparoscopic left adrenalectomy. The resected left adrenal gland weighed 54 g, and the tumor measured 65 × 50 × 30 mm. Representative histological findings are illustrated in Fig. 2C and 2D. The histological features of the tumor in the left adrenal gland were similar to those in the right adrenal gland. The tumor on the left side was also diagnosed as an adrenocortical adenoma. No cysts were discernible in the left resected specimen, and most of the left adrenal glands remained intact.
In addition to the hematoxylin-eosin stain, we immunolocalized steroidogenic enzymes in both the resected adrenal glands (Figs. 3-5). In both tumors, immunoreactivity of 3β-hydroxysteroid dehydrogenase (HSD3β), 17α-hydroxylase, and 11β-hydroxylase (Fig. 3A and 3D) was diffusely detected but that of CYP11β2 [9, 11] was not (Fig. 3B and 3E). These results demonstrate that the tumor cells could produce cortisol but not aldosterone. Immunoreactivity of dehydroepiandrosterone-sulfotransferase (DHEA-ST) in the zona reticularis of the attached nonneoplastic adrenal cortex, which reflects the long-term dynamics of the hypothalamus-pituitary-adrenal (HPA) axis, was within normal limits (Fig. 3C and 3F). Therefore, cortisol produced by these tumors did not affect the HPA axis in the patient. Ki-67 labeling indices were 2.5% in the right adrenal tumor and less than 1% in the left adrenal tumor. The right-sided cysts were diagnosed as endothelial cysts because the monolayer lining cells were positive for CD31 immunoreactivity (Fig. 4). The nonneoplastic adrenal glands adjacent to the tumors on both sides had similar pathological features: morphologically hyperplastic in the zona glomerulosa (immunohistochemically positive for HSD3β and CYP11β2 [Fig. 3B and 3E and Fig. 5]) [9]. The final diagnosis of the resected adrenal glands following detailed analyses of steroidogenesis was that of a bilateral nonfunctional adrenocortical adenoma with cortisol-producing ability, with endothelial cyst formation and bilateral diffuse hyperplasia of the zona glomerulosa in the adjacent nonneoplastic adrenal glands.
Figure 3. Photomicrograph of the resected tumors and adrenal glands in A to C, the right side and D to F, the left side. A and D, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). The zona fasciculata and zona reticularis of the adrenal glands were positive for CYP11β1. Tumors were also positive for CYP11β1. B and E, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). Lined positivity for CYP11β2 of the zona glomerulosa was detected (blue arrows). Tumors were negative for CYP11β2. C and F, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST). The zona reticularis of the adrenal glands was positive for DHEA-ST. Tumors were negative for DHEA-ST.
Figure 4. Photomicrograph of the right-sided cystic region (immunohistochemical labeling for CD31). The monolayer lining cells of the cyst wall were CD31 positive, indicating endothelial cysts.
Figure 5. Photomicrograph of the resected intact adrenal tissue. Morphologically hyperplastic feature was detected in the zona glomerulosa. A, Hematoxylin-eosin staining. B, Immunohistochemical labeling for 11β-hydroxylase (CYP11β1). C, Immunohistochemical labeling for 18-hydroxylase: aldosterone synthase (CYP11β2). D, Immunohistochemical labeling for dehydroepiandrosterone-sulfotransferase (DHEA-ST).
The postoperative course of the patient was uneventful. Hydrocortisone replacement was continued. Fludrocortisone was not administered according to a clinical practice guideline on primary adrenal insufficiency by the Japan Endocrine Society [12]. However, the clinical practice guideline of the Endocrine Society recommends mineral corticoid replacement with fludrocortisone and no restriction on salt intake [13]. Her blood pressure was 102 to 120/56 to 80 mm Hg. The patient’s blood biochemistry data were almost within the normal range. Fasting blood glucose and hemoglobin A1c levels were improved, reaching 100 mg/dL and 6.5%, respectively, without the administration of SGLT2 inhibitor or other diabetic medications (empagliflozin was stopped before the first surgery). This remission of diabetes might be caused by the reduction of body weight and cessation of the exogenous glucocorticoid.
2. Discussion
In our case, the adrenal glands showed relatively large bilateral adrenal incidentalomas (measuring 6.2 × 2.5 cm on the right side and 4.6 × 4.1 cm on the left side) and unilateral cysts on the right side. In addition, these tumor masses showed a density of 30 to 50 H on the right side and 10 to 40 H on the left side on CT. To date, 24% of adrenal incidentalomas measuring more than 4 cm in diameter have been reported as being malignant lesions, with 90% of adrenal carcinomas having been reported to be larger than 4 cm in diameter [14]. The lipid content of the adrenal mass results in low attenuation on CT, which enables the distinction of adenomas from nonadenomas; adenomas have low attenuation (≤ 10 H) on CT [14]. Moreover, discerning the malignancy of the adrenal cystic lesions precisely, without histological diagnosis, is difficult [15]. Furthermore, the prevalence of benign adrenal cortical adenomas has been reported to increase with age [14]. In our case, surgical excision was based on the following conditions: surgical removal should be considered for nonfunctional adrenal masses measuring more than 4 cm unless there is a clear benign cause [16, 17] and should also be considered for masses measuring more than 4.6 cm or more than 20 H on CT [18]. In addition, because adrenal carcinomas could be associated with benign-appearing cysts, whole-specimen exploration of resected tissues is definitively recommended to rule out malignancy [19].
We performed multiple scans: CT, MRI, and PET. When an adrenal tumor has a large size and high attenuation as detected by CT scan, surgery without multiple scans was an appropriate option. If this case showed single laterality, we would proceed to surgery without multiple scans. However, this case manifested as a bilateral adrenal tumor. We tried to investigate the possibility of leaving the adrenal gland on the one side and begin with surgical resection of the other, but eventually surgery on both sides was needed. This is the reason for undertaking multiple scans and the separate adrenalectomies.
Approximately 15% of adrenal incidentalomas have been reported to be bilateral [14, 16]. In bilateral cases, adrenocortical hypofunction could occur owing to the damage of normal adrenal glands by tumor masses; therefore, screening of the adrenal glands’ function has been recommended [14, 16]. Adrenocortical hypofunction was observed in our case during the preoperative diagnosis. Based on low serum cortisol levels and the results of the ACTH and CRH load test, secondary but not primary adrenal insufficiency was suspected as being the cause of adrenocortical hypofunction. In fact, the postoperative histological study revealed almost intact adrenal glands and bilateral adenomas, with cortisol-producing potential, which did not influence the HPA axis because of normal histological features of the zona fasciculata and reticularis and intact expression of DHEA-ST in the zona reticularis. Therefore, the adrenal insufficiency in this case might have been caused by the temporary use of an exogeneous glucocorticoid and not by direct damage to the adrenal glands by bilateral tumors.
Adrenal endothelial cysts are rare diseases, and cases complicated with adrenal neoplasms are known to be extremely rare [6, 8], with a female predominance and a right-sided prevalence [7], as observed in our case. The pathogenesis of an endothelial cyst with an adrenocortical adenoma has been speculated by a previous study: local circulatory failure by repeated cycles of thrombus formation and recanalization and blood flow communication to a preexisting hemangioma [6].
In our case, in addition to bilateral adrenocortical adenoma with endothelial cysts, morphologically and immunohistochemically confirmed diffuse adrenal hyperplasia of the zona glomerulosa was detected. Although serum aldosterone levels, serum renin activity, and blood pressure were all within the normal range, detailed examination of the resected adrenal gland revealed diffuse hyperplasia of the zona glomerulosa, which was diffusely positive for CYP11β2. High sodium intake in the modern lifestyle has been reported to diminish the area of zona glomerulosa with aging [20, 21] as the renin-angiotensin-aldosterone system (RAAS) is relatively suppressed [20]. Consequently, elderly people usually have a smaller area of zona glomerulosa. Hyperplasia of the zona glomerulosa was detected during excessive activation of the RAAS, which further results in secondary aldosteronism [20]. The patient in our study did not have diseases causing secondary aldosteronism, but one possibility for the activated RAAS was the use of empagliflozin, an SGLT2 inhibitor, which led to diffuse hyperplasia of the zona glomerulosa. Serum renin and aldosterone levels have been reported to increase significantly with SGLT2 inhibitor use within 1 month, which is associated with a decrease in extracellular fluid [22, 23]. Inconsistent results have been reported for the changes in RAAS in long-term treatments with SGLT2 inhibitors [24]. Although renin activity and aldosterone levels both were reported to normalize after 6 months of SGLT2 inhibitor treatment in some studies [22], increased RAAS activation after 24 weeks of SGLT2 inhibitor treatment was reported in another study [25]. Dehydration is one of the most frequent adverse events of SGLT2 inhibitor use [26, 27] due to the excretion of abundant urinary glucose. In our case, although serum renin and aldosterone levels were within the normal range, urine aldosterone level was above normal, and serum aldosterone level was close to the upper limit of the normal range. In addition, our patient had increased blood hemoglobin and hematocrit levels (15.0-15.7g/dL and 43.5%-46.4%, respectively), which suggest dehydration associated with SGLT2 inhibitor treatment before the operation, which returned to normal levels (13.9-14.5g/dL and 40.5%-42.6%, respectively) after discontinuation of the SGLT2 inhibitor post operation. In our study, surgical resection of the bilateral adrenal glands for the treatment of an adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine the morphology and histology of adrenal glands under SGLT2 inhibitor treatment, leading to unexpected findings of diffuse bilateral hyperplasia of the zona glomerulosa, with no functional changes in renin and aldosterone levels, and no increase in blood pressure. These results suggest the possibility of SGLT2 inhibitors having some effect on the zona glomerulosa of the adrenal gland; for instance, the latent loss of plasma volume caused by the SGLT2 inhibitor stimulating the zona glomerulosa chronically, leading to hyperplasia.
3. Conclusion
To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts coexisted, demonstrating the complexity and difficulty of preoperative diagnosis of bilateral adrenal incidentaloma. The adrenal mass in our case was not malignant, but a large tumor with cysts should be considered for resection because potential malignancy is ruled out by detailed histopathological evaluation of the lesions. In addition, surgical resection of bilateral adrenal glands for the treatment of adrenocortical adenoma with endothelial cysts enabled us, for the first time, to examine in detail the morphology and histology of the adrenal glands under SGLT2 inhibitor treatment, leading to an unexpected finding of diffuse bilateral hyperplasia of the zona glomerulosa in nonneoplastic adrenal glands, without clinically demonstrating primary aldosteronism. Therefore, we advocate a new hypothesis that SGLT2 inhibitors affect the zona glomerulosa of the adrenal gland; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of zona glomerulosa based on the data in this singular case. Because this can be confirmed only under limited conditions, additional case reports or animal model studies on adrenal gland histology under SGLT2 inhibition are warranted.
Acknowledgments
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Abbreviations
ACTH adrenocorticotropic hormone
CRH corticotropin-releasing hormone
CT computed tomography
CYP11β2 18-hydroxylase
DHEA-ST dehydroepiandrosterone-sulfotransferase
HPA hypothalamus-pituitary-adrenal
HSD3β 3β-hydroxysteroid dehydrogenase
H Hounsfield unit
MRI magnetic resonance imaging
PET positron emission tomography
RAAS renin-angiotensin-aldosterone system
SGLT2 sodium-glucose co-transport protein-2
Additional Information
Disclosure Summary: The authors have no conflicts of interest to report.
Data Availability
Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study. | Recovering | ReactionOutcome | CC BY-NC-ND | 33381672 | 19,439,388 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Insulinoma'. | Calcium Stimulation Test for Insulinoma Localization in an End-stage Renal Disease Patient on Diazoxide.
Insulinomas are rare, and even rarer in patients with end-stage renal disease (ESRD). Clear criteria for the biochemical diagnosis of insulinomas in patients with renal failure have not been established, and hypoglycemia is often attributed to the renal disease itself, frequently leading to a delay in diagnosis. We describe a case of a patient who presented with asymptomatic recurrent hypoglycemia during hemodialysis. Disease progression and biochemical testing strongly suggested an insulinoma. Computed tomography (CT) of the abdomen and pelvis, 111In-pentetreotide scintigraphy and endoscopic ultrasound did not localize a pancreatic tumor. A calcium stimulation test was performed while the patient was taking diazoxide due to severe hypoglycemia with fasting for a couple of hours without treatment. The test showed a marked increase in insulin after calcium infusion in the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland. Exploratory surgery easily identified a tumor at the body of the pancreas and pathology confirmed an insulin-secreting pancreatic neuroendocrine tumor. On follow-up, there was resolution of the hypoglycemia. We review the challenges of diagnosing an insulinoma in ESRD and describe a successful intra-arterial calcium stimulation test done in an ESRD patient while continuing diazoxide.
Insulinomas, while being the most common functioning islet cell tumors, are rare with an incidence of 4 per million persons [1]. They are exceedingly rare in patients with end-stage renal disease (ESRD), reported in just 7 patients, including 3 patients on hemodialysis and 1 patient on peritoneal dialysis [2–8]. Establishing the diagnosis of insulinoma is always challenging [9], and even more so in ESRD, where spontaneous hypoglycemia can be due to other factors, including decreased renal gluconeogenesis, impaired insulin clearance, decreased hepatic gluconeogenesis from uremia, an abnormal counter-regulatory hormone response, and malnutrition [2]. Hypoglycemia in ESRD is often attributed to these other causes, leading to missed or delayed diagnosis in cases of an insulinoma.
Once diagnosed, insulinomas are often difficult to localize. Several strategies exist for localizing difficult-to-find tumors, including intra-arterial calcium administration to arteries supplying the pancreas to stimulate insulin secretion from the tumor. Diazoxide, a potassium channel activator used to treat hyperinsulinemia, is usually discontinued during this testing so as not to suppress the insulin response to calcium. We report the first case of successful insulinoma localization from a calcium stimulation test performed in a patient with ESRD while continuing diazoxide.
Case Report
A 36-year-old man with ESRD due to systemic lupus erythematosus (SLE) and hypertension, on hemodialysis for 5 years, was referred to the San Francisco General Hospital Endocrine Clinic for recurrent hypoglycemia. During the previous 10 months, the patient was noted to have hypoglycemia on multiple occasions during hemodialysis with nonfasting serum blood glucoses (BG) ranging from 30 to 40 mg/dL. He denied symptoms other than weakness during these episodes. A cortisol level obtained during 1 instance of hypoglycemia (BG 34 mg/dL) was 14.7 mg/dL, which, given the degree of hypoglycemia, suggested possible adrenal insufficiency. His medications were benazepril 20 mg daily and cinacalcet 30 mg daily. He did have a history of prior prednisone use for many years for his SLE, but he had not been taking it for at least several months prior to presentation. There was no family history of endocrine disorders.
The patient was admitted to the hospital for a supervised fast. Physical examination was unremarkable. After 4.5 hours of fasting he became confused, diaphoretic, and irritable. Blood glucose was 27 mg/dL. Symptoms resolved with treatment of the hypoglycemia, thus establishing Whipple’s triad. When BG was 27 mg/dL, other labs included insulin 19.8 μU/mL (ref 3–25), C-peptide 7.6 ng/mL (ref 0.8–3.5), proinsulin 385.5 pmol/L (ref < 26.8), and beta-hydroxybutyrate 0.07 mmol/L (ref < 0.28). Sulfonylurea panel and insulin autoantibody were negative. These results are typically diagnostic of an insulinoma (criteria: BG < 55 mg/dL, insulin ≥ 3.0 μU/mL, C-peptide ≥ 0.6 ng/mL, proinsulin ≥ 5 pmol/L, and beta-hydroxybutyrate levels ≤ 2.7 mmol/L) [9]. However, in ESRD, endogenous glucose production, from both the kidney and liver, is reduced, contributing to fasting hypoglycemia. While insulin secretion should be quickly suppressed with hypoglycemia, because of delayed insulin clearance in ESRD, insulin concentrations can remain elevated and further contribute to hypoglycemia. Unfortunately, no clear diagnostic criteria exist for appropriate insulin suppression in ESRD. For our patient, given his ESRD and possible mild adrenal insufficiency (discussed below), the diagnosis of an insulinoma remained uncertain.
During hospitalization the patient had a cosyntropin stimulation test that showed a precortisol level of 8.5 ug/dL, with an adrenocorticotropic hormone (ACTH) level of 55 pg/mL (ref 7–69 pg/mL; Siemens Immulite Assay; Siemens, Malvern, PA) and a postcortisol level of 15.8 ug/dL. This was deemed an insufficient response, especially in the setting of recurrent hypoglycemia. A 21-hydroxylase antibody test was negative and an abdominal computed tomography (CT) scan did not identify a pancreatic islet-cell tumor. He was therefore discharged home on hydrocortisone and diazoxide, with resolution of his hypoglycemic episodes. Repeat cosyntropin stimulation testing was performed on him as an outpatient 8 months later, with a precortisol level of 16.1 ug/dL and a postcortisol level of 20.3 ug/dL. It was presumed the patient had recovered from possible adrenal suppression from prior high-dose glucocorticoid use and hydrocortisone was subsequently discontinued. Further imaging with an octreotide scan and endoscopic ultrasound was performed and did not localize a pancreatic tumor. The patient refused referral for surgical exploration and did not follow-up further with endocrinology for several years.
As a side note, subsequent repeat ACTH several years later, again with the Siemens Immulite assay, was 236 pg/mL, with a corresponding cortisol of 16.8 ug/dL. This result was considered spurious given the cortisol and low clinical suspicion for adrenal insufficiency at the time. He had remained off prednisone and hydrocortisone. Subsequently, after it was reported that the Siemens Immulite ACTH assay could cause erroneously elevated results [10], this was rechecked using the Roche Cobas ACTH assay (Roche Diagnostics, Mannheim, Germany). The ACTH was actually borderline low at 5.4 pg/mL (ref 7.2–63.3 pg/mL), with a corresponding cortisol of 12.7. This suggests the original ACTH readings had been erroneously high and the patient may have initially had some degree of mild adrenal dysfunction due to his prior glucocorticoid use, which resolved with time.
Two years after his initial evaluation, the patient re-presented to the endocrine clinic with worsening hypoglycemia and frequent emergency room visits for nocturnal hypoglycemia with loss of consciousness. He also had a 50-pound weight gain due to eating and drinking soda every 4 hours. He had self-increased his diazoxide to 150 mg at night with minimal improvement in symptoms. Repeat endoscopic ultrasound and CT abdomen pelvis did not reveal a pancreatic lesion.
To localize the insulinoma, an intra-arterial calcium stimulation test was performed. Due to a hypoglycemic episode to 30 mg/dL while fasting in preparation for a CT scan, it was deemed unsafe to discontinue diazoxide during the calcium stimulation test. The patient fasted for 12 hours but took diazoxide 150 mg the night before and 50 mg on the morning of the procedure. The gastroduodenal, proper hepatic, superior mesenteric, and dorsal pancreatic arteries were catheterized with calcium gluconate bolused into each artery. Blood samples from the right hepatic vein were obtained at baseline and at 30, 60, 90, 120, and 150 seconds after injection. Notably, the majority of the blood supply to the body and tail of the pancreas was identified on angiography to originate from the dorsal pancreatic artery rather than branches from the splenic artery, as is more typically seen (Fig. 1). The results of the intra-arterial calcium stimulation showed a step-up in insulin from a baseline of 7.2 μU/L to a peak of 886.7 μU/L 90 seconds after injection of the dorsal pancreatic artery (Fig. 2). Injection in the other arteries showed no significant increase. The capillary BG decreased to 36 mg/dL with the surge in insulin. The patient reported tremors and diaphoresis and intravenous glucose (25 gm) was administered, with improvement in his symptoms. He was monitored postprocedure and his BG remained low at 44 mg/dL 4 hours later, likely due to the very high insulin level from the stimulation test and slow insulin clearance due to his renal failure. He was given an additional 25 grams of intravenous glucose and food, and his BG rose to 118 mg/dL. He refused to remain in the hospital and left against medical advice.
Figure 1. Visceral arteriogram demonstrates the tip of the catheter in the dorsal pancreatic artery (long white arrow). In this patient, the dorsal pancreatic artery is the dominant supply to the neck and body of the pancreas via the pancreatica magna artery (short white arrow) and transverse pancreatic artery (black arrow). Contrast is seen refluxing in the splenic artery (asterisk), which does not show significant supply to the pancreas.
Figure 2. Insulin in hepatic vein over time following arterial calcium gluconate stimulation.
The patient was referred to surgery for exploration and presumed resection of the distal pancreas. While awaiting surgery, whole body 68Gallium (68Ga)-DOTATATE (a radioconjugate with a high affinity to somatostatin receptor 2 positron emission tomography (PET)/CT scan [11]) became available under a research protocol. A radiotracer avid lesion was seen at the level of the body of the pancreas measuring 1.6 × 1.4 cm with a standardized uptake value of 32.2 (Fig. 3). Surgical laparoscopic exploration revealed an easily identifiable tumor situated directly over the body of the pancreas, and the patient underwent a distal pancreatectomy. Pathology showed a 1.9 × 1.2 × 1.2 cm well-differentiated tumor, with immunohistochemical staining positive for insulin, synaptophysin, chromogranin and a weak, patchy cytokeratin cocktail consistent with a low-grade insulin-secreting pancreatic neuroendocrine tumor. Postoperatively, the patient’s BG normalized with resolution of hypoglycemic symptoms and significant improvement in his quality of life. Notably, he lost 60 pounds 5 months postoperatively.
Figure 3. Whole body 68Gallium (68Ga)-DOTATATE showing a radiotracer avid lesion at the level of the body of the pancreas measuring 1.6 × 1.4 cm, with a standardized uptake value (SUV) of 32.2 (red arrow).
Discussion
Spontaneous hypoglycemia in ESRD is multifactorial and may occur due to reduced renal gluconeogenesis, decreased insulin clearance, reduced hepatic glucogenesis, impaired counterregulatory hormone response, diminished caloric intake, and the use of high glucose-containing dialysate during hemodialysis or peritoneal dialysis [2]. Thus, the diagnosis of endogenous hyperinsulinemia in the presence of ESRD is difficult and may be delayed without established criteria in this setting. Our patient had documented Whipple’s triad, though this can be seen in renal failure without the presence of an insulinoma. The clinical progression of his symptoms over several years with significant weight gain increased our suspicion for insulinoma. He initially responded well to diazoxide but 2 years later, re-presented with symptomatic hypoglycemia despite more aggressive diazoxide treatment.
As is common with insulinomas, initial localizing studies were negative. In these cases, an intra-arterial calcium stimulation test is reported to localize 88% to 100% of insulinomas to the correct region of the pancreas [11]. Understanding the arterial supply of the pancreas is important. Interestingly, in this case the patient displayed variable anatomy. His angiography showed no significant arterial supply to the pancreas from the splenic artery, which is normally the dominant blood supply to the body and tail of the pancreas. Rather, supply to this region appeared to originate from the dorsal pancreatic artery, which was selectively catheterized and bolused with calcium gluconate, along with the gastroduodenal, proper hepatic, and superior mesenteric arteries.
In pancreatic β-cells, glucose enters the cell and generates adenosine triphosphate (ATP), which closes the potassium ATP (KATP) channels. Cells are depolarized, voltage gated calcium channels open, and increased intracellular calcium leads to insulin release. Sulfonylureas bind to the KATP channels and also close them, thereby increasing insulin secretion. However, diazoxide opens the KATP channels, hyperpolarizing the cell, leading to the closure of voltage gated calcium channels, decreased intracellular calcium, and inhibition of insulin secretion. Thus, diazoxide is especially useful in the management of hyperinsulinism from an insulinoma [12]. However, in a patient undergoing a calcium stimulation test, calcium enters the pancreatic beta cells primarily through the voltage-activated calcium channels closed by diazoxide. In the presence of diazoxide, it would therefore be expected that insulinoma cells would be unresponsive to the increase in extracellular calcium. Accordingly, protocols for the calcium stimulation procedure dictate that diazoxide should be discontinued at the time of testing so as not to suppress insulin secretion.
For safety reasons, our patient was maintained on diazoxide, including on the morning of the test. This is the first report, to our knowledge, of a successful intra-arterial calcium stimulation test while continuing diazoxide treatment. Our patient showed marked elevation in insulin after calcium infusion into the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland, which corresponded to the tumor location at surgery. A previous study reported a false-negative selective arterial calcium stimulation in a patient maintained on diazoxide, and repeat testing in the same patient after diazoxide was discontinued and localized the insulinoma [13]. The reason for success with diazoxide in 1 patient but not the other is likely due to underlying differences in the tumors. It was first observed over 30 years ago that there are striking differences in insulinoma responsiveness to diazoxide [14]. Different subtypes of insulinomas have been proposed with different postulated mechanisms responsible for dysregulated insulin secretion [15]. Therefore, we hypothesize the tumor in our patient was relatively unresponsive to diazoxide. Patients with diazoxide-unresponsive tumors also tended to have relatively higher proinsulin concentrations, as was the case in our patient [14]. Unresponsiveness to diazoxide is further supported by the severe hypoglycemia requiring frequent eating despite treatment. All of these factors may have allowed for successful arterial calcium stimulation, though future studies will be needed to determine how best to identify patients who can have successful tumor localization while still taking diazoxide.
Of note, had it been available earlier, 68Ga-DOTATATE PET/CT would also have revealed the tumor location, forgoing the need for calcium stimulation. 68Ga-DOTATATE PET/CT identifies most insulinomas with better accuracy than CT, magnetic resonance imaging (MRI), ultrasound, and octreotide scintigraphy [16]. Therefore, while selective arterial secretagogue injection remains more accurate for regionalizing insulinomas [17], it may be used much less frequently. 111In-DTPA-exendin-4 SPECT/CT, used for glucagon-like-peptide-1 receptor imaging, is also known to be a more sensitive modality for the localization of insulinomas compared with traditional imaging methods.
Our case highlights that in ESRD, there will be a significant risk for prolonged postprocedure hypoglycemia given a delay in clearance of the very high circulating insulin concentrations. In our patient, this hypoglycemia risk lasted at least 4 hours. Given he left against advice, we don’t know how much longer this may have lasted. Postprocedural-prolonged hypoglycemia in ESRD should be anticipated and patients should be monitored for many hours postprocedure. Consideration of overnight observation may be appropriate.
This case shows that while diazoxide is traditionally not used with an intra-arterial calcium stimulation test, it can be continued in some cases of severe hypoglycemia with successful results. Insulinoma in the setting of ESRD is rare and difficult to diagnosis, often leading to a delay in treatment. It is important to note that clearance of insulin after the calcium stimulation may be slow and patients need to be closely monitored for a prolonged period postprocedure to ensure that glucose levels are stable.
Additional Information
Disclosure Summary: The authors have nothing to disclose.
Data Availability
Some or all data generated or analyzed during this study are included in this published article or in the data repositories listed in References. | BENAZEPRIL HYDROCHLORIDE, CINACALCET HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33381673 | 19,399,600 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional product use issue'. | Calcium Stimulation Test for Insulinoma Localization in an End-stage Renal Disease Patient on Diazoxide.
Insulinomas are rare, and even rarer in patients with end-stage renal disease (ESRD). Clear criteria for the biochemical diagnosis of insulinomas in patients with renal failure have not been established, and hypoglycemia is often attributed to the renal disease itself, frequently leading to a delay in diagnosis. We describe a case of a patient who presented with asymptomatic recurrent hypoglycemia during hemodialysis. Disease progression and biochemical testing strongly suggested an insulinoma. Computed tomography (CT) of the abdomen and pelvis, 111In-pentetreotide scintigraphy and endoscopic ultrasound did not localize a pancreatic tumor. A calcium stimulation test was performed while the patient was taking diazoxide due to severe hypoglycemia with fasting for a couple of hours without treatment. The test showed a marked increase in insulin after calcium infusion in the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland. Exploratory surgery easily identified a tumor at the body of the pancreas and pathology confirmed an insulin-secreting pancreatic neuroendocrine tumor. On follow-up, there was resolution of the hypoglycemia. We review the challenges of diagnosing an insulinoma in ESRD and describe a successful intra-arterial calcium stimulation test done in an ESRD patient while continuing diazoxide.
Insulinomas, while being the most common functioning islet cell tumors, are rare with an incidence of 4 per million persons [1]. They are exceedingly rare in patients with end-stage renal disease (ESRD), reported in just 7 patients, including 3 patients on hemodialysis and 1 patient on peritoneal dialysis [2–8]. Establishing the diagnosis of insulinoma is always challenging [9], and even more so in ESRD, where spontaneous hypoglycemia can be due to other factors, including decreased renal gluconeogenesis, impaired insulin clearance, decreased hepatic gluconeogenesis from uremia, an abnormal counter-regulatory hormone response, and malnutrition [2]. Hypoglycemia in ESRD is often attributed to these other causes, leading to missed or delayed diagnosis in cases of an insulinoma.
Once diagnosed, insulinomas are often difficult to localize. Several strategies exist for localizing difficult-to-find tumors, including intra-arterial calcium administration to arteries supplying the pancreas to stimulate insulin secretion from the tumor. Diazoxide, a potassium channel activator used to treat hyperinsulinemia, is usually discontinued during this testing so as not to suppress the insulin response to calcium. We report the first case of successful insulinoma localization from a calcium stimulation test performed in a patient with ESRD while continuing diazoxide.
Case Report
A 36-year-old man with ESRD due to systemic lupus erythematosus (SLE) and hypertension, on hemodialysis for 5 years, was referred to the San Francisco General Hospital Endocrine Clinic for recurrent hypoglycemia. During the previous 10 months, the patient was noted to have hypoglycemia on multiple occasions during hemodialysis with nonfasting serum blood glucoses (BG) ranging from 30 to 40 mg/dL. He denied symptoms other than weakness during these episodes. A cortisol level obtained during 1 instance of hypoglycemia (BG 34 mg/dL) was 14.7 mg/dL, which, given the degree of hypoglycemia, suggested possible adrenal insufficiency. His medications were benazepril 20 mg daily and cinacalcet 30 mg daily. He did have a history of prior prednisone use for many years for his SLE, but he had not been taking it for at least several months prior to presentation. There was no family history of endocrine disorders.
The patient was admitted to the hospital for a supervised fast. Physical examination was unremarkable. After 4.5 hours of fasting he became confused, diaphoretic, and irritable. Blood glucose was 27 mg/dL. Symptoms resolved with treatment of the hypoglycemia, thus establishing Whipple’s triad. When BG was 27 mg/dL, other labs included insulin 19.8 μU/mL (ref 3–25), C-peptide 7.6 ng/mL (ref 0.8–3.5), proinsulin 385.5 pmol/L (ref < 26.8), and beta-hydroxybutyrate 0.07 mmol/L (ref < 0.28). Sulfonylurea panel and insulin autoantibody were negative. These results are typically diagnostic of an insulinoma (criteria: BG < 55 mg/dL, insulin ≥ 3.0 μU/mL, C-peptide ≥ 0.6 ng/mL, proinsulin ≥ 5 pmol/L, and beta-hydroxybutyrate levels ≤ 2.7 mmol/L) [9]. However, in ESRD, endogenous glucose production, from both the kidney and liver, is reduced, contributing to fasting hypoglycemia. While insulin secretion should be quickly suppressed with hypoglycemia, because of delayed insulin clearance in ESRD, insulin concentrations can remain elevated and further contribute to hypoglycemia. Unfortunately, no clear diagnostic criteria exist for appropriate insulin suppression in ESRD. For our patient, given his ESRD and possible mild adrenal insufficiency (discussed below), the diagnosis of an insulinoma remained uncertain.
During hospitalization the patient had a cosyntropin stimulation test that showed a precortisol level of 8.5 ug/dL, with an adrenocorticotropic hormone (ACTH) level of 55 pg/mL (ref 7–69 pg/mL; Siemens Immulite Assay; Siemens, Malvern, PA) and a postcortisol level of 15.8 ug/dL. This was deemed an insufficient response, especially in the setting of recurrent hypoglycemia. A 21-hydroxylase antibody test was negative and an abdominal computed tomography (CT) scan did not identify a pancreatic islet-cell tumor. He was therefore discharged home on hydrocortisone and diazoxide, with resolution of his hypoglycemic episodes. Repeat cosyntropin stimulation testing was performed on him as an outpatient 8 months later, with a precortisol level of 16.1 ug/dL and a postcortisol level of 20.3 ug/dL. It was presumed the patient had recovered from possible adrenal suppression from prior high-dose glucocorticoid use and hydrocortisone was subsequently discontinued. Further imaging with an octreotide scan and endoscopic ultrasound was performed and did not localize a pancreatic tumor. The patient refused referral for surgical exploration and did not follow-up further with endocrinology for several years.
As a side note, subsequent repeat ACTH several years later, again with the Siemens Immulite assay, was 236 pg/mL, with a corresponding cortisol of 16.8 ug/dL. This result was considered spurious given the cortisol and low clinical suspicion for adrenal insufficiency at the time. He had remained off prednisone and hydrocortisone. Subsequently, after it was reported that the Siemens Immulite ACTH assay could cause erroneously elevated results [10], this was rechecked using the Roche Cobas ACTH assay (Roche Diagnostics, Mannheim, Germany). The ACTH was actually borderline low at 5.4 pg/mL (ref 7.2–63.3 pg/mL), with a corresponding cortisol of 12.7. This suggests the original ACTH readings had been erroneously high and the patient may have initially had some degree of mild adrenal dysfunction due to his prior glucocorticoid use, which resolved with time.
Two years after his initial evaluation, the patient re-presented to the endocrine clinic with worsening hypoglycemia and frequent emergency room visits for nocturnal hypoglycemia with loss of consciousness. He also had a 50-pound weight gain due to eating and drinking soda every 4 hours. He had self-increased his diazoxide to 150 mg at night with minimal improvement in symptoms. Repeat endoscopic ultrasound and CT abdomen pelvis did not reveal a pancreatic lesion.
To localize the insulinoma, an intra-arterial calcium stimulation test was performed. Due to a hypoglycemic episode to 30 mg/dL while fasting in preparation for a CT scan, it was deemed unsafe to discontinue diazoxide during the calcium stimulation test. The patient fasted for 12 hours but took diazoxide 150 mg the night before and 50 mg on the morning of the procedure. The gastroduodenal, proper hepatic, superior mesenteric, and dorsal pancreatic arteries were catheterized with calcium gluconate bolused into each artery. Blood samples from the right hepatic vein were obtained at baseline and at 30, 60, 90, 120, and 150 seconds after injection. Notably, the majority of the blood supply to the body and tail of the pancreas was identified on angiography to originate from the dorsal pancreatic artery rather than branches from the splenic artery, as is more typically seen (Fig. 1). The results of the intra-arterial calcium stimulation showed a step-up in insulin from a baseline of 7.2 μU/L to a peak of 886.7 μU/L 90 seconds after injection of the dorsal pancreatic artery (Fig. 2). Injection in the other arteries showed no significant increase. The capillary BG decreased to 36 mg/dL with the surge in insulin. The patient reported tremors and diaphoresis and intravenous glucose (25 gm) was administered, with improvement in his symptoms. He was monitored postprocedure and his BG remained low at 44 mg/dL 4 hours later, likely due to the very high insulin level from the stimulation test and slow insulin clearance due to his renal failure. He was given an additional 25 grams of intravenous glucose and food, and his BG rose to 118 mg/dL. He refused to remain in the hospital and left against medical advice.
Figure 1. Visceral arteriogram demonstrates the tip of the catheter in the dorsal pancreatic artery (long white arrow). In this patient, the dorsal pancreatic artery is the dominant supply to the neck and body of the pancreas via the pancreatica magna artery (short white arrow) and transverse pancreatic artery (black arrow). Contrast is seen refluxing in the splenic artery (asterisk), which does not show significant supply to the pancreas.
Figure 2. Insulin in hepatic vein over time following arterial calcium gluconate stimulation.
The patient was referred to surgery for exploration and presumed resection of the distal pancreas. While awaiting surgery, whole body 68Gallium (68Ga)-DOTATATE (a radioconjugate with a high affinity to somatostatin receptor 2 positron emission tomography (PET)/CT scan [11]) became available under a research protocol. A radiotracer avid lesion was seen at the level of the body of the pancreas measuring 1.6 × 1.4 cm with a standardized uptake value of 32.2 (Fig. 3). Surgical laparoscopic exploration revealed an easily identifiable tumor situated directly over the body of the pancreas, and the patient underwent a distal pancreatectomy. Pathology showed a 1.9 × 1.2 × 1.2 cm well-differentiated tumor, with immunohistochemical staining positive for insulin, synaptophysin, chromogranin and a weak, patchy cytokeratin cocktail consistent with a low-grade insulin-secreting pancreatic neuroendocrine tumor. Postoperatively, the patient’s BG normalized with resolution of hypoglycemic symptoms and significant improvement in his quality of life. Notably, he lost 60 pounds 5 months postoperatively.
Figure 3. Whole body 68Gallium (68Ga)-DOTATATE showing a radiotracer avid lesion at the level of the body of the pancreas measuring 1.6 × 1.4 cm, with a standardized uptake value (SUV) of 32.2 (red arrow).
Discussion
Spontaneous hypoglycemia in ESRD is multifactorial and may occur due to reduced renal gluconeogenesis, decreased insulin clearance, reduced hepatic glucogenesis, impaired counterregulatory hormone response, diminished caloric intake, and the use of high glucose-containing dialysate during hemodialysis or peritoneal dialysis [2]. Thus, the diagnosis of endogenous hyperinsulinemia in the presence of ESRD is difficult and may be delayed without established criteria in this setting. Our patient had documented Whipple’s triad, though this can be seen in renal failure without the presence of an insulinoma. The clinical progression of his symptoms over several years with significant weight gain increased our suspicion for insulinoma. He initially responded well to diazoxide but 2 years later, re-presented with symptomatic hypoglycemia despite more aggressive diazoxide treatment.
As is common with insulinomas, initial localizing studies were negative. In these cases, an intra-arterial calcium stimulation test is reported to localize 88% to 100% of insulinomas to the correct region of the pancreas [11]. Understanding the arterial supply of the pancreas is important. Interestingly, in this case the patient displayed variable anatomy. His angiography showed no significant arterial supply to the pancreas from the splenic artery, which is normally the dominant blood supply to the body and tail of the pancreas. Rather, supply to this region appeared to originate from the dorsal pancreatic artery, which was selectively catheterized and bolused with calcium gluconate, along with the gastroduodenal, proper hepatic, and superior mesenteric arteries.
In pancreatic β-cells, glucose enters the cell and generates adenosine triphosphate (ATP), which closes the potassium ATP (KATP) channels. Cells are depolarized, voltage gated calcium channels open, and increased intracellular calcium leads to insulin release. Sulfonylureas bind to the KATP channels and also close them, thereby increasing insulin secretion. However, diazoxide opens the KATP channels, hyperpolarizing the cell, leading to the closure of voltage gated calcium channels, decreased intracellular calcium, and inhibition of insulin secretion. Thus, diazoxide is especially useful in the management of hyperinsulinism from an insulinoma [12]. However, in a patient undergoing a calcium stimulation test, calcium enters the pancreatic beta cells primarily through the voltage-activated calcium channels closed by diazoxide. In the presence of diazoxide, it would therefore be expected that insulinoma cells would be unresponsive to the increase in extracellular calcium. Accordingly, protocols for the calcium stimulation procedure dictate that diazoxide should be discontinued at the time of testing so as not to suppress insulin secretion.
For safety reasons, our patient was maintained on diazoxide, including on the morning of the test. This is the first report, to our knowledge, of a successful intra-arterial calcium stimulation test while continuing diazoxide treatment. Our patient showed marked elevation in insulin after calcium infusion into the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland, which corresponded to the tumor location at surgery. A previous study reported a false-negative selective arterial calcium stimulation in a patient maintained on diazoxide, and repeat testing in the same patient after diazoxide was discontinued and localized the insulinoma [13]. The reason for success with diazoxide in 1 patient but not the other is likely due to underlying differences in the tumors. It was first observed over 30 years ago that there are striking differences in insulinoma responsiveness to diazoxide [14]. Different subtypes of insulinomas have been proposed with different postulated mechanisms responsible for dysregulated insulin secretion [15]. Therefore, we hypothesize the tumor in our patient was relatively unresponsive to diazoxide. Patients with diazoxide-unresponsive tumors also tended to have relatively higher proinsulin concentrations, as was the case in our patient [14]. Unresponsiveness to diazoxide is further supported by the severe hypoglycemia requiring frequent eating despite treatment. All of these factors may have allowed for successful arterial calcium stimulation, though future studies will be needed to determine how best to identify patients who can have successful tumor localization while still taking diazoxide.
Of note, had it been available earlier, 68Ga-DOTATATE PET/CT would also have revealed the tumor location, forgoing the need for calcium stimulation. 68Ga-DOTATATE PET/CT identifies most insulinomas with better accuracy than CT, magnetic resonance imaging (MRI), ultrasound, and octreotide scintigraphy [16]. Therefore, while selective arterial secretagogue injection remains more accurate for regionalizing insulinomas [17], it may be used much less frequently. 111In-DTPA-exendin-4 SPECT/CT, used for glucagon-like-peptide-1 receptor imaging, is also known to be a more sensitive modality for the localization of insulinomas compared with traditional imaging methods.
Our case highlights that in ESRD, there will be a significant risk for prolonged postprocedure hypoglycemia given a delay in clearance of the very high circulating insulin concentrations. In our patient, this hypoglycemia risk lasted at least 4 hours. Given he left against advice, we don’t know how much longer this may have lasted. Postprocedural-prolonged hypoglycemia in ESRD should be anticipated and patients should be monitored for many hours postprocedure. Consideration of overnight observation may be appropriate.
This case shows that while diazoxide is traditionally not used with an intra-arterial calcium stimulation test, it can be continued in some cases of severe hypoglycemia with successful results. Insulinoma in the setting of ESRD is rare and difficult to diagnosis, often leading to a delay in treatment. It is important to note that clearance of insulin after the calcium stimulation may be slow and patients need to be closely monitored for a prolonged period postprocedure to ensure that glucose levels are stable.
Additional Information
Disclosure Summary: The authors have nothing to disclose.
Data Availability
Some or all data generated or analyzed during this study are included in this published article or in the data repositories listed in References. | BENAZEPRIL HYDROCHLORIDE, CINACALCET, DIAZOXIDE, HYDROCORTISONE, PREDNISONE | DrugsGivenReaction | CC BY-NC-ND | 33381673 | 19,631,669 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Wrong technique in product usage process'. | Calcium Stimulation Test for Insulinoma Localization in an End-stage Renal Disease Patient on Diazoxide.
Insulinomas are rare, and even rarer in patients with end-stage renal disease (ESRD). Clear criteria for the biochemical diagnosis of insulinomas in patients with renal failure have not been established, and hypoglycemia is often attributed to the renal disease itself, frequently leading to a delay in diagnosis. We describe a case of a patient who presented with asymptomatic recurrent hypoglycemia during hemodialysis. Disease progression and biochemical testing strongly suggested an insulinoma. Computed tomography (CT) of the abdomen and pelvis, 111In-pentetreotide scintigraphy and endoscopic ultrasound did not localize a pancreatic tumor. A calcium stimulation test was performed while the patient was taking diazoxide due to severe hypoglycemia with fasting for a couple of hours without treatment. The test showed a marked increase in insulin after calcium infusion in the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland. Exploratory surgery easily identified a tumor at the body of the pancreas and pathology confirmed an insulin-secreting pancreatic neuroendocrine tumor. On follow-up, there was resolution of the hypoglycemia. We review the challenges of diagnosing an insulinoma in ESRD and describe a successful intra-arterial calcium stimulation test done in an ESRD patient while continuing diazoxide.
Insulinomas, while being the most common functioning islet cell tumors, are rare with an incidence of 4 per million persons [1]. They are exceedingly rare in patients with end-stage renal disease (ESRD), reported in just 7 patients, including 3 patients on hemodialysis and 1 patient on peritoneal dialysis [2–8]. Establishing the diagnosis of insulinoma is always challenging [9], and even more so in ESRD, where spontaneous hypoglycemia can be due to other factors, including decreased renal gluconeogenesis, impaired insulin clearance, decreased hepatic gluconeogenesis from uremia, an abnormal counter-regulatory hormone response, and malnutrition [2]. Hypoglycemia in ESRD is often attributed to these other causes, leading to missed or delayed diagnosis in cases of an insulinoma.
Once diagnosed, insulinomas are often difficult to localize. Several strategies exist for localizing difficult-to-find tumors, including intra-arterial calcium administration to arteries supplying the pancreas to stimulate insulin secretion from the tumor. Diazoxide, a potassium channel activator used to treat hyperinsulinemia, is usually discontinued during this testing so as not to suppress the insulin response to calcium. We report the first case of successful insulinoma localization from a calcium stimulation test performed in a patient with ESRD while continuing diazoxide.
Case Report
A 36-year-old man with ESRD due to systemic lupus erythematosus (SLE) and hypertension, on hemodialysis for 5 years, was referred to the San Francisco General Hospital Endocrine Clinic for recurrent hypoglycemia. During the previous 10 months, the patient was noted to have hypoglycemia on multiple occasions during hemodialysis with nonfasting serum blood glucoses (BG) ranging from 30 to 40 mg/dL. He denied symptoms other than weakness during these episodes. A cortisol level obtained during 1 instance of hypoglycemia (BG 34 mg/dL) was 14.7 mg/dL, which, given the degree of hypoglycemia, suggested possible adrenal insufficiency. His medications were benazepril 20 mg daily and cinacalcet 30 mg daily. He did have a history of prior prednisone use for many years for his SLE, but he had not been taking it for at least several months prior to presentation. There was no family history of endocrine disorders.
The patient was admitted to the hospital for a supervised fast. Physical examination was unremarkable. After 4.5 hours of fasting he became confused, diaphoretic, and irritable. Blood glucose was 27 mg/dL. Symptoms resolved with treatment of the hypoglycemia, thus establishing Whipple’s triad. When BG was 27 mg/dL, other labs included insulin 19.8 μU/mL (ref 3–25), C-peptide 7.6 ng/mL (ref 0.8–3.5), proinsulin 385.5 pmol/L (ref < 26.8), and beta-hydroxybutyrate 0.07 mmol/L (ref < 0.28). Sulfonylurea panel and insulin autoantibody were negative. These results are typically diagnostic of an insulinoma (criteria: BG < 55 mg/dL, insulin ≥ 3.0 μU/mL, C-peptide ≥ 0.6 ng/mL, proinsulin ≥ 5 pmol/L, and beta-hydroxybutyrate levels ≤ 2.7 mmol/L) [9]. However, in ESRD, endogenous glucose production, from both the kidney and liver, is reduced, contributing to fasting hypoglycemia. While insulin secretion should be quickly suppressed with hypoglycemia, because of delayed insulin clearance in ESRD, insulin concentrations can remain elevated and further contribute to hypoglycemia. Unfortunately, no clear diagnostic criteria exist for appropriate insulin suppression in ESRD. For our patient, given his ESRD and possible mild adrenal insufficiency (discussed below), the diagnosis of an insulinoma remained uncertain.
During hospitalization the patient had a cosyntropin stimulation test that showed a precortisol level of 8.5 ug/dL, with an adrenocorticotropic hormone (ACTH) level of 55 pg/mL (ref 7–69 pg/mL; Siemens Immulite Assay; Siemens, Malvern, PA) and a postcortisol level of 15.8 ug/dL. This was deemed an insufficient response, especially in the setting of recurrent hypoglycemia. A 21-hydroxylase antibody test was negative and an abdominal computed tomography (CT) scan did not identify a pancreatic islet-cell tumor. He was therefore discharged home on hydrocortisone and diazoxide, with resolution of his hypoglycemic episodes. Repeat cosyntropin stimulation testing was performed on him as an outpatient 8 months later, with a precortisol level of 16.1 ug/dL and a postcortisol level of 20.3 ug/dL. It was presumed the patient had recovered from possible adrenal suppression from prior high-dose glucocorticoid use and hydrocortisone was subsequently discontinued. Further imaging with an octreotide scan and endoscopic ultrasound was performed and did not localize a pancreatic tumor. The patient refused referral for surgical exploration and did not follow-up further with endocrinology for several years.
As a side note, subsequent repeat ACTH several years later, again with the Siemens Immulite assay, was 236 pg/mL, with a corresponding cortisol of 16.8 ug/dL. This result was considered spurious given the cortisol and low clinical suspicion for adrenal insufficiency at the time. He had remained off prednisone and hydrocortisone. Subsequently, after it was reported that the Siemens Immulite ACTH assay could cause erroneously elevated results [10], this was rechecked using the Roche Cobas ACTH assay (Roche Diagnostics, Mannheim, Germany). The ACTH was actually borderline low at 5.4 pg/mL (ref 7.2–63.3 pg/mL), with a corresponding cortisol of 12.7. This suggests the original ACTH readings had been erroneously high and the patient may have initially had some degree of mild adrenal dysfunction due to his prior glucocorticoid use, which resolved with time.
Two years after his initial evaluation, the patient re-presented to the endocrine clinic with worsening hypoglycemia and frequent emergency room visits for nocturnal hypoglycemia with loss of consciousness. He also had a 50-pound weight gain due to eating and drinking soda every 4 hours. He had self-increased his diazoxide to 150 mg at night with minimal improvement in symptoms. Repeat endoscopic ultrasound and CT abdomen pelvis did not reveal a pancreatic lesion.
To localize the insulinoma, an intra-arterial calcium stimulation test was performed. Due to a hypoglycemic episode to 30 mg/dL while fasting in preparation for a CT scan, it was deemed unsafe to discontinue diazoxide during the calcium stimulation test. The patient fasted for 12 hours but took diazoxide 150 mg the night before and 50 mg on the morning of the procedure. The gastroduodenal, proper hepatic, superior mesenteric, and dorsal pancreatic arteries were catheterized with calcium gluconate bolused into each artery. Blood samples from the right hepatic vein were obtained at baseline and at 30, 60, 90, 120, and 150 seconds after injection. Notably, the majority of the blood supply to the body and tail of the pancreas was identified on angiography to originate from the dorsal pancreatic artery rather than branches from the splenic artery, as is more typically seen (Fig. 1). The results of the intra-arterial calcium stimulation showed a step-up in insulin from a baseline of 7.2 μU/L to a peak of 886.7 μU/L 90 seconds after injection of the dorsal pancreatic artery (Fig. 2). Injection in the other arteries showed no significant increase. The capillary BG decreased to 36 mg/dL with the surge in insulin. The patient reported tremors and diaphoresis and intravenous glucose (25 gm) was administered, with improvement in his symptoms. He was monitored postprocedure and his BG remained low at 44 mg/dL 4 hours later, likely due to the very high insulin level from the stimulation test and slow insulin clearance due to his renal failure. He was given an additional 25 grams of intravenous glucose and food, and his BG rose to 118 mg/dL. He refused to remain in the hospital and left against medical advice.
Figure 1. Visceral arteriogram demonstrates the tip of the catheter in the dorsal pancreatic artery (long white arrow). In this patient, the dorsal pancreatic artery is the dominant supply to the neck and body of the pancreas via the pancreatica magna artery (short white arrow) and transverse pancreatic artery (black arrow). Contrast is seen refluxing in the splenic artery (asterisk), which does not show significant supply to the pancreas.
Figure 2. Insulin in hepatic vein over time following arterial calcium gluconate stimulation.
The patient was referred to surgery for exploration and presumed resection of the distal pancreas. While awaiting surgery, whole body 68Gallium (68Ga)-DOTATATE (a radioconjugate with a high affinity to somatostatin receptor 2 positron emission tomography (PET)/CT scan [11]) became available under a research protocol. A radiotracer avid lesion was seen at the level of the body of the pancreas measuring 1.6 × 1.4 cm with a standardized uptake value of 32.2 (Fig. 3). Surgical laparoscopic exploration revealed an easily identifiable tumor situated directly over the body of the pancreas, and the patient underwent a distal pancreatectomy. Pathology showed a 1.9 × 1.2 × 1.2 cm well-differentiated tumor, with immunohistochemical staining positive for insulin, synaptophysin, chromogranin and a weak, patchy cytokeratin cocktail consistent with a low-grade insulin-secreting pancreatic neuroendocrine tumor. Postoperatively, the patient’s BG normalized with resolution of hypoglycemic symptoms and significant improvement in his quality of life. Notably, he lost 60 pounds 5 months postoperatively.
Figure 3. Whole body 68Gallium (68Ga)-DOTATATE showing a radiotracer avid lesion at the level of the body of the pancreas measuring 1.6 × 1.4 cm, with a standardized uptake value (SUV) of 32.2 (red arrow).
Discussion
Spontaneous hypoglycemia in ESRD is multifactorial and may occur due to reduced renal gluconeogenesis, decreased insulin clearance, reduced hepatic glucogenesis, impaired counterregulatory hormone response, diminished caloric intake, and the use of high glucose-containing dialysate during hemodialysis or peritoneal dialysis [2]. Thus, the diagnosis of endogenous hyperinsulinemia in the presence of ESRD is difficult and may be delayed without established criteria in this setting. Our patient had documented Whipple’s triad, though this can be seen in renal failure without the presence of an insulinoma. The clinical progression of his symptoms over several years with significant weight gain increased our suspicion for insulinoma. He initially responded well to diazoxide but 2 years later, re-presented with symptomatic hypoglycemia despite more aggressive diazoxide treatment.
As is common with insulinomas, initial localizing studies were negative. In these cases, an intra-arterial calcium stimulation test is reported to localize 88% to 100% of insulinomas to the correct region of the pancreas [11]. Understanding the arterial supply of the pancreas is important. Interestingly, in this case the patient displayed variable anatomy. His angiography showed no significant arterial supply to the pancreas from the splenic artery, which is normally the dominant blood supply to the body and tail of the pancreas. Rather, supply to this region appeared to originate from the dorsal pancreatic artery, which was selectively catheterized and bolused with calcium gluconate, along with the gastroduodenal, proper hepatic, and superior mesenteric arteries.
In pancreatic β-cells, glucose enters the cell and generates adenosine triphosphate (ATP), which closes the potassium ATP (KATP) channels. Cells are depolarized, voltage gated calcium channels open, and increased intracellular calcium leads to insulin release. Sulfonylureas bind to the KATP channels and also close them, thereby increasing insulin secretion. However, diazoxide opens the KATP channels, hyperpolarizing the cell, leading to the closure of voltage gated calcium channels, decreased intracellular calcium, and inhibition of insulin secretion. Thus, diazoxide is especially useful in the management of hyperinsulinism from an insulinoma [12]. However, in a patient undergoing a calcium stimulation test, calcium enters the pancreatic beta cells primarily through the voltage-activated calcium channels closed by diazoxide. In the presence of diazoxide, it would therefore be expected that insulinoma cells would be unresponsive to the increase in extracellular calcium. Accordingly, protocols for the calcium stimulation procedure dictate that diazoxide should be discontinued at the time of testing so as not to suppress insulin secretion.
For safety reasons, our patient was maintained on diazoxide, including on the morning of the test. This is the first report, to our knowledge, of a successful intra-arterial calcium stimulation test while continuing diazoxide treatment. Our patient showed marked elevation in insulin after calcium infusion into the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland, which corresponded to the tumor location at surgery. A previous study reported a false-negative selective arterial calcium stimulation in a patient maintained on diazoxide, and repeat testing in the same patient after diazoxide was discontinued and localized the insulinoma [13]. The reason for success with diazoxide in 1 patient but not the other is likely due to underlying differences in the tumors. It was first observed over 30 years ago that there are striking differences in insulinoma responsiveness to diazoxide [14]. Different subtypes of insulinomas have been proposed with different postulated mechanisms responsible for dysregulated insulin secretion [15]. Therefore, we hypothesize the tumor in our patient was relatively unresponsive to diazoxide. Patients with diazoxide-unresponsive tumors also tended to have relatively higher proinsulin concentrations, as was the case in our patient [14]. Unresponsiveness to diazoxide is further supported by the severe hypoglycemia requiring frequent eating despite treatment. All of these factors may have allowed for successful arterial calcium stimulation, though future studies will be needed to determine how best to identify patients who can have successful tumor localization while still taking diazoxide.
Of note, had it been available earlier, 68Ga-DOTATATE PET/CT would also have revealed the tumor location, forgoing the need for calcium stimulation. 68Ga-DOTATATE PET/CT identifies most insulinomas with better accuracy than CT, magnetic resonance imaging (MRI), ultrasound, and octreotide scintigraphy [16]. Therefore, while selective arterial secretagogue injection remains more accurate for regionalizing insulinomas [17], it may be used much less frequently. 111In-DTPA-exendin-4 SPECT/CT, used for glucagon-like-peptide-1 receptor imaging, is also known to be a more sensitive modality for the localization of insulinomas compared with traditional imaging methods.
Our case highlights that in ESRD, there will be a significant risk for prolonged postprocedure hypoglycemia given a delay in clearance of the very high circulating insulin concentrations. In our patient, this hypoglycemia risk lasted at least 4 hours. Given he left against advice, we don’t know how much longer this may have lasted. Postprocedural-prolonged hypoglycemia in ESRD should be anticipated and patients should be monitored for many hours postprocedure. Consideration of overnight observation may be appropriate.
This case shows that while diazoxide is traditionally not used with an intra-arterial calcium stimulation test, it can be continued in some cases of severe hypoglycemia with successful results. Insulinoma in the setting of ESRD is rare and difficult to diagnosis, often leading to a delay in treatment. It is important to note that clearance of insulin after the calcium stimulation may be slow and patients need to be closely monitored for a prolonged period postprocedure to ensure that glucose levels are stable.
Additional Information
Disclosure Summary: The authors have nothing to disclose.
Data Availability
Some or all data generated or analyzed during this study are included in this published article or in the data repositories listed in References. | BENAZEPRIL HYDROCHLORIDE, CINACALCET, DIAZOXIDE, HYDROCORTISONE, PREDNISONE | DrugsGivenReaction | CC BY-NC-ND | 33381673 | 19,631,669 | 2021-02-01 |
What was the outcome of reaction 'Adrenal insufficiency'? | Calcium Stimulation Test for Insulinoma Localization in an End-stage Renal Disease Patient on Diazoxide.
Insulinomas are rare, and even rarer in patients with end-stage renal disease (ESRD). Clear criteria for the biochemical diagnosis of insulinomas in patients with renal failure have not been established, and hypoglycemia is often attributed to the renal disease itself, frequently leading to a delay in diagnosis. We describe a case of a patient who presented with asymptomatic recurrent hypoglycemia during hemodialysis. Disease progression and biochemical testing strongly suggested an insulinoma. Computed tomography (CT) of the abdomen and pelvis, 111In-pentetreotide scintigraphy and endoscopic ultrasound did not localize a pancreatic tumor. A calcium stimulation test was performed while the patient was taking diazoxide due to severe hypoglycemia with fasting for a couple of hours without treatment. The test showed a marked increase in insulin after calcium infusion in the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland. Exploratory surgery easily identified a tumor at the body of the pancreas and pathology confirmed an insulin-secreting pancreatic neuroendocrine tumor. On follow-up, there was resolution of the hypoglycemia. We review the challenges of diagnosing an insulinoma in ESRD and describe a successful intra-arterial calcium stimulation test done in an ESRD patient while continuing diazoxide.
Insulinomas, while being the most common functioning islet cell tumors, are rare with an incidence of 4 per million persons [1]. They are exceedingly rare in patients with end-stage renal disease (ESRD), reported in just 7 patients, including 3 patients on hemodialysis and 1 patient on peritoneal dialysis [2–8]. Establishing the diagnosis of insulinoma is always challenging [9], and even more so in ESRD, where spontaneous hypoglycemia can be due to other factors, including decreased renal gluconeogenesis, impaired insulin clearance, decreased hepatic gluconeogenesis from uremia, an abnormal counter-regulatory hormone response, and malnutrition [2]. Hypoglycemia in ESRD is often attributed to these other causes, leading to missed or delayed diagnosis in cases of an insulinoma.
Once diagnosed, insulinomas are often difficult to localize. Several strategies exist for localizing difficult-to-find tumors, including intra-arterial calcium administration to arteries supplying the pancreas to stimulate insulin secretion from the tumor. Diazoxide, a potassium channel activator used to treat hyperinsulinemia, is usually discontinued during this testing so as not to suppress the insulin response to calcium. We report the first case of successful insulinoma localization from a calcium stimulation test performed in a patient with ESRD while continuing diazoxide.
Case Report
A 36-year-old man with ESRD due to systemic lupus erythematosus (SLE) and hypertension, on hemodialysis for 5 years, was referred to the San Francisco General Hospital Endocrine Clinic for recurrent hypoglycemia. During the previous 10 months, the patient was noted to have hypoglycemia on multiple occasions during hemodialysis with nonfasting serum blood glucoses (BG) ranging from 30 to 40 mg/dL. He denied symptoms other than weakness during these episodes. A cortisol level obtained during 1 instance of hypoglycemia (BG 34 mg/dL) was 14.7 mg/dL, which, given the degree of hypoglycemia, suggested possible adrenal insufficiency. His medications were benazepril 20 mg daily and cinacalcet 30 mg daily. He did have a history of prior prednisone use for many years for his SLE, but he had not been taking it for at least several months prior to presentation. There was no family history of endocrine disorders.
The patient was admitted to the hospital for a supervised fast. Physical examination was unremarkable. After 4.5 hours of fasting he became confused, diaphoretic, and irritable. Blood glucose was 27 mg/dL. Symptoms resolved with treatment of the hypoglycemia, thus establishing Whipple’s triad. When BG was 27 mg/dL, other labs included insulin 19.8 μU/mL (ref 3–25), C-peptide 7.6 ng/mL (ref 0.8–3.5), proinsulin 385.5 pmol/L (ref < 26.8), and beta-hydroxybutyrate 0.07 mmol/L (ref < 0.28). Sulfonylurea panel and insulin autoantibody were negative. These results are typically diagnostic of an insulinoma (criteria: BG < 55 mg/dL, insulin ≥ 3.0 μU/mL, C-peptide ≥ 0.6 ng/mL, proinsulin ≥ 5 pmol/L, and beta-hydroxybutyrate levels ≤ 2.7 mmol/L) [9]. However, in ESRD, endogenous glucose production, from both the kidney and liver, is reduced, contributing to fasting hypoglycemia. While insulin secretion should be quickly suppressed with hypoglycemia, because of delayed insulin clearance in ESRD, insulin concentrations can remain elevated and further contribute to hypoglycemia. Unfortunately, no clear diagnostic criteria exist for appropriate insulin suppression in ESRD. For our patient, given his ESRD and possible mild adrenal insufficiency (discussed below), the diagnosis of an insulinoma remained uncertain.
During hospitalization the patient had a cosyntropin stimulation test that showed a precortisol level of 8.5 ug/dL, with an adrenocorticotropic hormone (ACTH) level of 55 pg/mL (ref 7–69 pg/mL; Siemens Immulite Assay; Siemens, Malvern, PA) and a postcortisol level of 15.8 ug/dL. This was deemed an insufficient response, especially in the setting of recurrent hypoglycemia. A 21-hydroxylase antibody test was negative and an abdominal computed tomography (CT) scan did not identify a pancreatic islet-cell tumor. He was therefore discharged home on hydrocortisone and diazoxide, with resolution of his hypoglycemic episodes. Repeat cosyntropin stimulation testing was performed on him as an outpatient 8 months later, with a precortisol level of 16.1 ug/dL and a postcortisol level of 20.3 ug/dL. It was presumed the patient had recovered from possible adrenal suppression from prior high-dose glucocorticoid use and hydrocortisone was subsequently discontinued. Further imaging with an octreotide scan and endoscopic ultrasound was performed and did not localize a pancreatic tumor. The patient refused referral for surgical exploration and did not follow-up further with endocrinology for several years.
As a side note, subsequent repeat ACTH several years later, again with the Siemens Immulite assay, was 236 pg/mL, with a corresponding cortisol of 16.8 ug/dL. This result was considered spurious given the cortisol and low clinical suspicion for adrenal insufficiency at the time. He had remained off prednisone and hydrocortisone. Subsequently, after it was reported that the Siemens Immulite ACTH assay could cause erroneously elevated results [10], this was rechecked using the Roche Cobas ACTH assay (Roche Diagnostics, Mannheim, Germany). The ACTH was actually borderline low at 5.4 pg/mL (ref 7.2–63.3 pg/mL), with a corresponding cortisol of 12.7. This suggests the original ACTH readings had been erroneously high and the patient may have initially had some degree of mild adrenal dysfunction due to his prior glucocorticoid use, which resolved with time.
Two years after his initial evaluation, the patient re-presented to the endocrine clinic with worsening hypoglycemia and frequent emergency room visits for nocturnal hypoglycemia with loss of consciousness. He also had a 50-pound weight gain due to eating and drinking soda every 4 hours. He had self-increased his diazoxide to 150 mg at night with minimal improvement in symptoms. Repeat endoscopic ultrasound and CT abdomen pelvis did not reveal a pancreatic lesion.
To localize the insulinoma, an intra-arterial calcium stimulation test was performed. Due to a hypoglycemic episode to 30 mg/dL while fasting in preparation for a CT scan, it was deemed unsafe to discontinue diazoxide during the calcium stimulation test. The patient fasted for 12 hours but took diazoxide 150 mg the night before and 50 mg on the morning of the procedure. The gastroduodenal, proper hepatic, superior mesenteric, and dorsal pancreatic arteries were catheterized with calcium gluconate bolused into each artery. Blood samples from the right hepatic vein were obtained at baseline and at 30, 60, 90, 120, and 150 seconds after injection. Notably, the majority of the blood supply to the body and tail of the pancreas was identified on angiography to originate from the dorsal pancreatic artery rather than branches from the splenic artery, as is more typically seen (Fig. 1). The results of the intra-arterial calcium stimulation showed a step-up in insulin from a baseline of 7.2 μU/L to a peak of 886.7 μU/L 90 seconds after injection of the dorsal pancreatic artery (Fig. 2). Injection in the other arteries showed no significant increase. The capillary BG decreased to 36 mg/dL with the surge in insulin. The patient reported tremors and diaphoresis and intravenous glucose (25 gm) was administered, with improvement in his symptoms. He was monitored postprocedure and his BG remained low at 44 mg/dL 4 hours later, likely due to the very high insulin level from the stimulation test and slow insulin clearance due to his renal failure. He was given an additional 25 grams of intravenous glucose and food, and his BG rose to 118 mg/dL. He refused to remain in the hospital and left against medical advice.
Figure 1. Visceral arteriogram demonstrates the tip of the catheter in the dorsal pancreatic artery (long white arrow). In this patient, the dorsal pancreatic artery is the dominant supply to the neck and body of the pancreas via the pancreatica magna artery (short white arrow) and transverse pancreatic artery (black arrow). Contrast is seen refluxing in the splenic artery (asterisk), which does not show significant supply to the pancreas.
Figure 2. Insulin in hepatic vein over time following arterial calcium gluconate stimulation.
The patient was referred to surgery for exploration and presumed resection of the distal pancreas. While awaiting surgery, whole body 68Gallium (68Ga)-DOTATATE (a radioconjugate with a high affinity to somatostatin receptor 2 positron emission tomography (PET)/CT scan [11]) became available under a research protocol. A radiotracer avid lesion was seen at the level of the body of the pancreas measuring 1.6 × 1.4 cm with a standardized uptake value of 32.2 (Fig. 3). Surgical laparoscopic exploration revealed an easily identifiable tumor situated directly over the body of the pancreas, and the patient underwent a distal pancreatectomy. Pathology showed a 1.9 × 1.2 × 1.2 cm well-differentiated tumor, with immunohistochemical staining positive for insulin, synaptophysin, chromogranin and a weak, patchy cytokeratin cocktail consistent with a low-grade insulin-secreting pancreatic neuroendocrine tumor. Postoperatively, the patient’s BG normalized with resolution of hypoglycemic symptoms and significant improvement in his quality of life. Notably, he lost 60 pounds 5 months postoperatively.
Figure 3. Whole body 68Gallium (68Ga)-DOTATATE showing a radiotracer avid lesion at the level of the body of the pancreas measuring 1.6 × 1.4 cm, with a standardized uptake value (SUV) of 32.2 (red arrow).
Discussion
Spontaneous hypoglycemia in ESRD is multifactorial and may occur due to reduced renal gluconeogenesis, decreased insulin clearance, reduced hepatic glucogenesis, impaired counterregulatory hormone response, diminished caloric intake, and the use of high glucose-containing dialysate during hemodialysis or peritoneal dialysis [2]. Thus, the diagnosis of endogenous hyperinsulinemia in the presence of ESRD is difficult and may be delayed without established criteria in this setting. Our patient had documented Whipple’s triad, though this can be seen in renal failure without the presence of an insulinoma. The clinical progression of his symptoms over several years with significant weight gain increased our suspicion for insulinoma. He initially responded well to diazoxide but 2 years later, re-presented with symptomatic hypoglycemia despite more aggressive diazoxide treatment.
As is common with insulinomas, initial localizing studies were negative. In these cases, an intra-arterial calcium stimulation test is reported to localize 88% to 100% of insulinomas to the correct region of the pancreas [11]. Understanding the arterial supply of the pancreas is important. Interestingly, in this case the patient displayed variable anatomy. His angiography showed no significant arterial supply to the pancreas from the splenic artery, which is normally the dominant blood supply to the body and tail of the pancreas. Rather, supply to this region appeared to originate from the dorsal pancreatic artery, which was selectively catheterized and bolused with calcium gluconate, along with the gastroduodenal, proper hepatic, and superior mesenteric arteries.
In pancreatic β-cells, glucose enters the cell and generates adenosine triphosphate (ATP), which closes the potassium ATP (KATP) channels. Cells are depolarized, voltage gated calcium channels open, and increased intracellular calcium leads to insulin release. Sulfonylureas bind to the KATP channels and also close them, thereby increasing insulin secretion. However, diazoxide opens the KATP channels, hyperpolarizing the cell, leading to the closure of voltage gated calcium channels, decreased intracellular calcium, and inhibition of insulin secretion. Thus, diazoxide is especially useful in the management of hyperinsulinism from an insulinoma [12]. However, in a patient undergoing a calcium stimulation test, calcium enters the pancreatic beta cells primarily through the voltage-activated calcium channels closed by diazoxide. In the presence of diazoxide, it would therefore be expected that insulinoma cells would be unresponsive to the increase in extracellular calcium. Accordingly, protocols for the calcium stimulation procedure dictate that diazoxide should be discontinued at the time of testing so as not to suppress insulin secretion.
For safety reasons, our patient was maintained on diazoxide, including on the morning of the test. This is the first report, to our knowledge, of a successful intra-arterial calcium stimulation test while continuing diazoxide treatment. Our patient showed marked elevation in insulin after calcium infusion into the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland, which corresponded to the tumor location at surgery. A previous study reported a false-negative selective arterial calcium stimulation in a patient maintained on diazoxide, and repeat testing in the same patient after diazoxide was discontinued and localized the insulinoma [13]. The reason for success with diazoxide in 1 patient but not the other is likely due to underlying differences in the tumors. It was first observed over 30 years ago that there are striking differences in insulinoma responsiveness to diazoxide [14]. Different subtypes of insulinomas have been proposed with different postulated mechanisms responsible for dysregulated insulin secretion [15]. Therefore, we hypothesize the tumor in our patient was relatively unresponsive to diazoxide. Patients with diazoxide-unresponsive tumors also tended to have relatively higher proinsulin concentrations, as was the case in our patient [14]. Unresponsiveness to diazoxide is further supported by the severe hypoglycemia requiring frequent eating despite treatment. All of these factors may have allowed for successful arterial calcium stimulation, though future studies will be needed to determine how best to identify patients who can have successful tumor localization while still taking diazoxide.
Of note, had it been available earlier, 68Ga-DOTATATE PET/CT would also have revealed the tumor location, forgoing the need for calcium stimulation. 68Ga-DOTATATE PET/CT identifies most insulinomas with better accuracy than CT, magnetic resonance imaging (MRI), ultrasound, and octreotide scintigraphy [16]. Therefore, while selective arterial secretagogue injection remains more accurate for regionalizing insulinomas [17], it may be used much less frequently. 111In-DTPA-exendin-4 SPECT/CT, used for glucagon-like-peptide-1 receptor imaging, is also known to be a more sensitive modality for the localization of insulinomas compared with traditional imaging methods.
Our case highlights that in ESRD, there will be a significant risk for prolonged postprocedure hypoglycemia given a delay in clearance of the very high circulating insulin concentrations. In our patient, this hypoglycemia risk lasted at least 4 hours. Given he left against advice, we don’t know how much longer this may have lasted. Postprocedural-prolonged hypoglycemia in ESRD should be anticipated and patients should be monitored for many hours postprocedure. Consideration of overnight observation may be appropriate.
This case shows that while diazoxide is traditionally not used with an intra-arterial calcium stimulation test, it can be continued in some cases of severe hypoglycemia with successful results. Insulinoma in the setting of ESRD is rare and difficult to diagnosis, often leading to a delay in treatment. It is important to note that clearance of insulin after the calcium stimulation may be slow and patients need to be closely monitored for a prolonged period postprocedure to ensure that glucose levels are stable.
Additional Information
Disclosure Summary: The authors have nothing to disclose.
Data Availability
Some or all data generated or analyzed during this study are included in this published article or in the data repositories listed in References. | Recovered | ReactionOutcome | CC BY-NC-ND | 33381673 | 19,631,669 | 2021-02-01 |
What was the outcome of reaction 'Insulinoma'? | Calcium Stimulation Test for Insulinoma Localization in an End-stage Renal Disease Patient on Diazoxide.
Insulinomas are rare, and even rarer in patients with end-stage renal disease (ESRD). Clear criteria for the biochemical diagnosis of insulinomas in patients with renal failure have not been established, and hypoglycemia is often attributed to the renal disease itself, frequently leading to a delay in diagnosis. We describe a case of a patient who presented with asymptomatic recurrent hypoglycemia during hemodialysis. Disease progression and biochemical testing strongly suggested an insulinoma. Computed tomography (CT) of the abdomen and pelvis, 111In-pentetreotide scintigraphy and endoscopic ultrasound did not localize a pancreatic tumor. A calcium stimulation test was performed while the patient was taking diazoxide due to severe hypoglycemia with fasting for a couple of hours without treatment. The test showed a marked increase in insulin after calcium infusion in the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland. Exploratory surgery easily identified a tumor at the body of the pancreas and pathology confirmed an insulin-secreting pancreatic neuroendocrine tumor. On follow-up, there was resolution of the hypoglycemia. We review the challenges of diagnosing an insulinoma in ESRD and describe a successful intra-arterial calcium stimulation test done in an ESRD patient while continuing diazoxide.
Insulinomas, while being the most common functioning islet cell tumors, are rare with an incidence of 4 per million persons [1]. They are exceedingly rare in patients with end-stage renal disease (ESRD), reported in just 7 patients, including 3 patients on hemodialysis and 1 patient on peritoneal dialysis [2–8]. Establishing the diagnosis of insulinoma is always challenging [9], and even more so in ESRD, where spontaneous hypoglycemia can be due to other factors, including decreased renal gluconeogenesis, impaired insulin clearance, decreased hepatic gluconeogenesis from uremia, an abnormal counter-regulatory hormone response, and malnutrition [2]. Hypoglycemia in ESRD is often attributed to these other causes, leading to missed or delayed diagnosis in cases of an insulinoma.
Once diagnosed, insulinomas are often difficult to localize. Several strategies exist for localizing difficult-to-find tumors, including intra-arterial calcium administration to arteries supplying the pancreas to stimulate insulin secretion from the tumor. Diazoxide, a potassium channel activator used to treat hyperinsulinemia, is usually discontinued during this testing so as not to suppress the insulin response to calcium. We report the first case of successful insulinoma localization from a calcium stimulation test performed in a patient with ESRD while continuing diazoxide.
Case Report
A 36-year-old man with ESRD due to systemic lupus erythematosus (SLE) and hypertension, on hemodialysis for 5 years, was referred to the San Francisco General Hospital Endocrine Clinic for recurrent hypoglycemia. During the previous 10 months, the patient was noted to have hypoglycemia on multiple occasions during hemodialysis with nonfasting serum blood glucoses (BG) ranging from 30 to 40 mg/dL. He denied symptoms other than weakness during these episodes. A cortisol level obtained during 1 instance of hypoglycemia (BG 34 mg/dL) was 14.7 mg/dL, which, given the degree of hypoglycemia, suggested possible adrenal insufficiency. His medications were benazepril 20 mg daily and cinacalcet 30 mg daily. He did have a history of prior prednisone use for many years for his SLE, but he had not been taking it for at least several months prior to presentation. There was no family history of endocrine disorders.
The patient was admitted to the hospital for a supervised fast. Physical examination was unremarkable. After 4.5 hours of fasting he became confused, diaphoretic, and irritable. Blood glucose was 27 mg/dL. Symptoms resolved with treatment of the hypoglycemia, thus establishing Whipple’s triad. When BG was 27 mg/dL, other labs included insulin 19.8 μU/mL (ref 3–25), C-peptide 7.6 ng/mL (ref 0.8–3.5), proinsulin 385.5 pmol/L (ref < 26.8), and beta-hydroxybutyrate 0.07 mmol/L (ref < 0.28). Sulfonylurea panel and insulin autoantibody were negative. These results are typically diagnostic of an insulinoma (criteria: BG < 55 mg/dL, insulin ≥ 3.0 μU/mL, C-peptide ≥ 0.6 ng/mL, proinsulin ≥ 5 pmol/L, and beta-hydroxybutyrate levels ≤ 2.7 mmol/L) [9]. However, in ESRD, endogenous glucose production, from both the kidney and liver, is reduced, contributing to fasting hypoglycemia. While insulin secretion should be quickly suppressed with hypoglycemia, because of delayed insulin clearance in ESRD, insulin concentrations can remain elevated and further contribute to hypoglycemia. Unfortunately, no clear diagnostic criteria exist for appropriate insulin suppression in ESRD. For our patient, given his ESRD and possible mild adrenal insufficiency (discussed below), the diagnosis of an insulinoma remained uncertain.
During hospitalization the patient had a cosyntropin stimulation test that showed a precortisol level of 8.5 ug/dL, with an adrenocorticotropic hormone (ACTH) level of 55 pg/mL (ref 7–69 pg/mL; Siemens Immulite Assay; Siemens, Malvern, PA) and a postcortisol level of 15.8 ug/dL. This was deemed an insufficient response, especially in the setting of recurrent hypoglycemia. A 21-hydroxylase antibody test was negative and an abdominal computed tomography (CT) scan did not identify a pancreatic islet-cell tumor. He was therefore discharged home on hydrocortisone and diazoxide, with resolution of his hypoglycemic episodes. Repeat cosyntropin stimulation testing was performed on him as an outpatient 8 months later, with a precortisol level of 16.1 ug/dL and a postcortisol level of 20.3 ug/dL. It was presumed the patient had recovered from possible adrenal suppression from prior high-dose glucocorticoid use and hydrocortisone was subsequently discontinued. Further imaging with an octreotide scan and endoscopic ultrasound was performed and did not localize a pancreatic tumor. The patient refused referral for surgical exploration and did not follow-up further with endocrinology for several years.
As a side note, subsequent repeat ACTH several years later, again with the Siemens Immulite assay, was 236 pg/mL, with a corresponding cortisol of 16.8 ug/dL. This result was considered spurious given the cortisol and low clinical suspicion for adrenal insufficiency at the time. He had remained off prednisone and hydrocortisone. Subsequently, after it was reported that the Siemens Immulite ACTH assay could cause erroneously elevated results [10], this was rechecked using the Roche Cobas ACTH assay (Roche Diagnostics, Mannheim, Germany). The ACTH was actually borderline low at 5.4 pg/mL (ref 7.2–63.3 pg/mL), with a corresponding cortisol of 12.7. This suggests the original ACTH readings had been erroneously high and the patient may have initially had some degree of mild adrenal dysfunction due to his prior glucocorticoid use, which resolved with time.
Two years after his initial evaluation, the patient re-presented to the endocrine clinic with worsening hypoglycemia and frequent emergency room visits for nocturnal hypoglycemia with loss of consciousness. He also had a 50-pound weight gain due to eating and drinking soda every 4 hours. He had self-increased his diazoxide to 150 mg at night with minimal improvement in symptoms. Repeat endoscopic ultrasound and CT abdomen pelvis did not reveal a pancreatic lesion.
To localize the insulinoma, an intra-arterial calcium stimulation test was performed. Due to a hypoglycemic episode to 30 mg/dL while fasting in preparation for a CT scan, it was deemed unsafe to discontinue diazoxide during the calcium stimulation test. The patient fasted for 12 hours but took diazoxide 150 mg the night before and 50 mg on the morning of the procedure. The gastroduodenal, proper hepatic, superior mesenteric, and dorsal pancreatic arteries were catheterized with calcium gluconate bolused into each artery. Blood samples from the right hepatic vein were obtained at baseline and at 30, 60, 90, 120, and 150 seconds after injection. Notably, the majority of the blood supply to the body and tail of the pancreas was identified on angiography to originate from the dorsal pancreatic artery rather than branches from the splenic artery, as is more typically seen (Fig. 1). The results of the intra-arterial calcium stimulation showed a step-up in insulin from a baseline of 7.2 μU/L to a peak of 886.7 μU/L 90 seconds after injection of the dorsal pancreatic artery (Fig. 2). Injection in the other arteries showed no significant increase. The capillary BG decreased to 36 mg/dL with the surge in insulin. The patient reported tremors and diaphoresis and intravenous glucose (25 gm) was administered, with improvement in his symptoms. He was monitored postprocedure and his BG remained low at 44 mg/dL 4 hours later, likely due to the very high insulin level from the stimulation test and slow insulin clearance due to his renal failure. He was given an additional 25 grams of intravenous glucose and food, and his BG rose to 118 mg/dL. He refused to remain in the hospital and left against medical advice.
Figure 1. Visceral arteriogram demonstrates the tip of the catheter in the dorsal pancreatic artery (long white arrow). In this patient, the dorsal pancreatic artery is the dominant supply to the neck and body of the pancreas via the pancreatica magna artery (short white arrow) and transverse pancreatic artery (black arrow). Contrast is seen refluxing in the splenic artery (asterisk), which does not show significant supply to the pancreas.
Figure 2. Insulin in hepatic vein over time following arterial calcium gluconate stimulation.
The patient was referred to surgery for exploration and presumed resection of the distal pancreas. While awaiting surgery, whole body 68Gallium (68Ga)-DOTATATE (a radioconjugate with a high affinity to somatostatin receptor 2 positron emission tomography (PET)/CT scan [11]) became available under a research protocol. A radiotracer avid lesion was seen at the level of the body of the pancreas measuring 1.6 × 1.4 cm with a standardized uptake value of 32.2 (Fig. 3). Surgical laparoscopic exploration revealed an easily identifiable tumor situated directly over the body of the pancreas, and the patient underwent a distal pancreatectomy. Pathology showed a 1.9 × 1.2 × 1.2 cm well-differentiated tumor, with immunohistochemical staining positive for insulin, synaptophysin, chromogranin and a weak, patchy cytokeratin cocktail consistent with a low-grade insulin-secreting pancreatic neuroendocrine tumor. Postoperatively, the patient’s BG normalized with resolution of hypoglycemic symptoms and significant improvement in his quality of life. Notably, he lost 60 pounds 5 months postoperatively.
Figure 3. Whole body 68Gallium (68Ga)-DOTATATE showing a radiotracer avid lesion at the level of the body of the pancreas measuring 1.6 × 1.4 cm, with a standardized uptake value (SUV) of 32.2 (red arrow).
Discussion
Spontaneous hypoglycemia in ESRD is multifactorial and may occur due to reduced renal gluconeogenesis, decreased insulin clearance, reduced hepatic glucogenesis, impaired counterregulatory hormone response, diminished caloric intake, and the use of high glucose-containing dialysate during hemodialysis or peritoneal dialysis [2]. Thus, the diagnosis of endogenous hyperinsulinemia in the presence of ESRD is difficult and may be delayed without established criteria in this setting. Our patient had documented Whipple’s triad, though this can be seen in renal failure without the presence of an insulinoma. The clinical progression of his symptoms over several years with significant weight gain increased our suspicion for insulinoma. He initially responded well to diazoxide but 2 years later, re-presented with symptomatic hypoglycemia despite more aggressive diazoxide treatment.
As is common with insulinomas, initial localizing studies were negative. In these cases, an intra-arterial calcium stimulation test is reported to localize 88% to 100% of insulinomas to the correct region of the pancreas [11]. Understanding the arterial supply of the pancreas is important. Interestingly, in this case the patient displayed variable anatomy. His angiography showed no significant arterial supply to the pancreas from the splenic artery, which is normally the dominant blood supply to the body and tail of the pancreas. Rather, supply to this region appeared to originate from the dorsal pancreatic artery, which was selectively catheterized and bolused with calcium gluconate, along with the gastroduodenal, proper hepatic, and superior mesenteric arteries.
In pancreatic β-cells, glucose enters the cell and generates adenosine triphosphate (ATP), which closes the potassium ATP (KATP) channels. Cells are depolarized, voltage gated calcium channels open, and increased intracellular calcium leads to insulin release. Sulfonylureas bind to the KATP channels and also close them, thereby increasing insulin secretion. However, diazoxide opens the KATP channels, hyperpolarizing the cell, leading to the closure of voltage gated calcium channels, decreased intracellular calcium, and inhibition of insulin secretion. Thus, diazoxide is especially useful in the management of hyperinsulinism from an insulinoma [12]. However, in a patient undergoing a calcium stimulation test, calcium enters the pancreatic beta cells primarily through the voltage-activated calcium channels closed by diazoxide. In the presence of diazoxide, it would therefore be expected that insulinoma cells would be unresponsive to the increase in extracellular calcium. Accordingly, protocols for the calcium stimulation procedure dictate that diazoxide should be discontinued at the time of testing so as not to suppress insulin secretion.
For safety reasons, our patient was maintained on diazoxide, including on the morning of the test. This is the first report, to our knowledge, of a successful intra-arterial calcium stimulation test while continuing diazoxide treatment. Our patient showed marked elevation in insulin after calcium infusion into the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland, which corresponded to the tumor location at surgery. A previous study reported a false-negative selective arterial calcium stimulation in a patient maintained on diazoxide, and repeat testing in the same patient after diazoxide was discontinued and localized the insulinoma [13]. The reason for success with diazoxide in 1 patient but not the other is likely due to underlying differences in the tumors. It was first observed over 30 years ago that there are striking differences in insulinoma responsiveness to diazoxide [14]. Different subtypes of insulinomas have been proposed with different postulated mechanisms responsible for dysregulated insulin secretion [15]. Therefore, we hypothesize the tumor in our patient was relatively unresponsive to diazoxide. Patients with diazoxide-unresponsive tumors also tended to have relatively higher proinsulin concentrations, as was the case in our patient [14]. Unresponsiveness to diazoxide is further supported by the severe hypoglycemia requiring frequent eating despite treatment. All of these factors may have allowed for successful arterial calcium stimulation, though future studies will be needed to determine how best to identify patients who can have successful tumor localization while still taking diazoxide.
Of note, had it been available earlier, 68Ga-DOTATATE PET/CT would also have revealed the tumor location, forgoing the need for calcium stimulation. 68Ga-DOTATATE PET/CT identifies most insulinomas with better accuracy than CT, magnetic resonance imaging (MRI), ultrasound, and octreotide scintigraphy [16]. Therefore, while selective arterial secretagogue injection remains more accurate for regionalizing insulinomas [17], it may be used much less frequently. 111In-DTPA-exendin-4 SPECT/CT, used for glucagon-like-peptide-1 receptor imaging, is also known to be a more sensitive modality for the localization of insulinomas compared with traditional imaging methods.
Our case highlights that in ESRD, there will be a significant risk for prolonged postprocedure hypoglycemia given a delay in clearance of the very high circulating insulin concentrations. In our patient, this hypoglycemia risk lasted at least 4 hours. Given he left against advice, we don’t know how much longer this may have lasted. Postprocedural-prolonged hypoglycemia in ESRD should be anticipated and patients should be monitored for many hours postprocedure. Consideration of overnight observation may be appropriate.
This case shows that while diazoxide is traditionally not used with an intra-arterial calcium stimulation test, it can be continued in some cases of severe hypoglycemia with successful results. Insulinoma in the setting of ESRD is rare and difficult to diagnosis, often leading to a delay in treatment. It is important to note that clearance of insulin after the calcium stimulation may be slow and patients need to be closely monitored for a prolonged period postprocedure to ensure that glucose levels are stable.
Additional Information
Disclosure Summary: The authors have nothing to disclose.
Data Availability
Some or all data generated or analyzed during this study are included in this published article or in the data repositories listed in References. | Recovered | ReactionOutcome | CC BY-NC-ND | 33381673 | 19,399,600 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | FUROSEMIDE, GADOTERATE MEGLUMINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hydronephrosis'. | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | FUROSEMIDE, GADOTERATE MEGLUMINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
What is the weight of the patient? | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | 21.3 kg. | Weight | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
What was the administration route of drug 'FUROSEMIDE'? | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
What was the administration route of drug 'GADOTERATE MEGLUMINE'? | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
What was the dosage of drug 'FUROSEMIDE'? | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | MAXIMUM 20 MG | DrugDosageText | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
What was the dosage of drug 'SODIUM CHLORIDE'? | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | 20 CC/KG OVER 45 MIN | DrugDosageText | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
What was the outcome of reaction 'Condition aggravated'? | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | Recovered | ReactionOutcome | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
What was the outcome of reaction 'Hydronephrosis'? | Dietl crisis: Presentation and imaging findings in a 7-year-old boy.
Intermittent ureteropelvic junction obstruction, or Dietl crisis, is a rare entity with sparse reports in published literature. Establishing the diagnosis is challenging given its intermittent nature. We report a case of Dietl crisis, focusing on ultrasound (US) and magnetic resonance urography (MRU) findings in a 7-year-old boy with recurrent episodes of colicky abdominal pain prompting multiple visits to the emergency department. Severe left hydronephrosis was visualized on US during one episode with complete resolution on follow-up US. MRU demonstrated severe left hydronephrosis with delayed calyceal transit time, time-to-peak enhancement, and excretion. There was no aberrant blood vessel. Surgical pyeloplasty provided complete symptomatic resolution. MRU can be a valuable tool in eliciting and dynamically confirming the diagnosis of Dietl crisis.
Introduction
Dietl crisis is a relatively rare entity, defined as intermittent ureteropelvic junction (UPJ) obstruction causing episodic abdominal pain, most often due to an aberrant accessory renal artery or vein [1]. It was first described in 1864 by Josef Dietl, who suggested initial conservative treatment or abdominal support with a belt or corset, as well as external application of pressure in the area of the affected kidney for prolonged pain [2]. Subsequently, from 1870 until the 1960s, surgical correction in the form of nephropexy was adopted [2]. More recently, laparoscopic pyeloplasty (with or without robotic assistance) has emerged as an adequate surgical intervention that causes complete resolution of symptoms in most cases [3]. While congenital UPJ obstruction is usually identified on routine prenatal ultrasound (US), some children present at an older age with episodes of abdominal or flank pain on the side of the obstruction, that may be associated with nausea and/or nonbilious vomiting, prompting multiple emergency department (ED) visits [4]. In view of complete symptom resolution with corrective surgery, accurate and prompt identification of patients with Dietl crisis with imaging tests becomes crucial. However, because of the vagueness of its presentation and the high frequency of nonspecific abdominal pain in school-aged children, routine abdominal US is not often performed and the diagnosis of Dietl's crisis is either delayed or missed [3]. The clinical differential diagnosis includes psychogenic pain, constipation, urinary tract infection, renal calculi, and appendicitis [1]. In the setting of high suspicion of Dietl crisis and when performed while symptomatic, US may identify obstructive hydronephrosis with dilatation of the renal pelvis and/or calyces, prompting further imaging such as computerized tomography, technetium-99m labeled mercaptoacetyltriglycerine (99mTc-MAG3) diuretic renography, or magnetic resonance urography (MRU) for anatomic and functional assessment of the pediatric urinary tract. We report a case of Dietl crisis in a 7-year-old boy while highlighting associated US and MRU findings.
Case Report
A previously healthy 7-year-old boy (weight = 21.3 kg; body surface area = 0.765 m2), with a normal antenatal US, presented to the ED with colicky left flank pain that began acutely a few hours prior to presentation. The pain was described as severe, waking him from sleep, and was associated with nausea and vomiting without fever, diarrhea, or urinary symptoms. The patient had previously presented to the ED with similar symptoms on two different occasions. On physical exam, left flank tenderness was noted on palpation with ipsilateral lower abdominal fullness. Complete blood count and basic metabolic panel were normal (Cr = 0.48 mg/dL). US examination of the kidneys was performed and demonstrated severe left hydronephrosis (Fig. 1a) without ureteral dilatation and a normal right kidney. Dietl crisis was suspected, and the patient was admitted to hospital for overnight observation and pain management. A follow-up US was performed 2 weeks later as an outpatient, showing complete resolution of left hydronephrosis (Fig. 1b).Fig. 1 Sagittal ultrasound of the left kidney performed at the time of presentation in the emergency department (a). The kidney demonstrated marked dilatation of the renal pelvis and calyces and measured 10.3 cm in length. Repeat ultrasound at outpatient follow-up visit 2 weeks after presentation (b) demonstrated resolution of the previously seen hydronephrosis in the affected kidney which measured 10.0 cm in length.
Fig 1
Pre- and postcontrast magnetic resonance imaging was performed based on the MRU protocol described by Dickerson et al. [5]. The patient was prehydrated with intravenous fluids (normal saline 20 cc/kg over 45 minutes). The MRU was performed under general anesthesia with a bladder catheter in place for the duration of the scan. Furosemide (1 mg/kg intravenous, max. 20 mg) was administered 15 minutes prior to gadolinium-based contrast (0.2 mL/kg intravenous, Dotarem, Guerbet). Sequential dynamic, coronal-oblique fat-saturation VIBE images were acquired before, during and after power injection of the intravenous contrast.
MRU demonstrated left hydronephrosis that gradually worsened in severity over the course of the scan (Fig. 2a and b) as the diuretic took effect. Arterial phase images showed no evidence of an aberrant blood vessel crossing the UPJ. Quantitative analysis was performed using Children's Hospital of Philadelphia Functional MRU analysis software (CHOP-fMRU, https://www.chop-fmru.com/) [6]. Renal parenchymal volume was found to be 77.9 mL on the right and 66.5 mL on the left. Differential renal function (DRF) was as follows: right-to-left ratio of 53.9%-46.1% using volumetric calculation (vDRF), 58.1% to 41.9% using Patlak calculation (pDRF), and 61.9%-38.1% using Volumetric-Patlak calculation (vpDRF). The difference between vDRF and pDRF (4.2%) was borderline significant (≥4%), suggesting decompensated hydronephrosis. Calyceal transit time (CTT) was delayed on the left (4 minutes 37 seconds) as compared to the right (2 minutes 13 seconds). Time to peak (TTP) of parenchymal enhancement was delayed on the left (5 minutes 33 seconds) as compared to the right (3 minutes 31 seconds). Excreted contrast reached the right proximal ureter (renal transit time, RTT) at 3 minutes 8 seconds. No excreted contrast was visualized in the left ureter over 34 minutes of postcontrast imaging, indicating UPJ obstruction. The delayed time values in the left kidney were further suggestive of decompensated hydronephrosis.Fig. 2 MRU performed under general anesthesia and with bladder catheterization. Furosemide was administered intravenously prior to contrast injection. Coronal T2 HASTE (a) and coronal T1 VIBE (b) images acquired 34 minutes after contrast administration demonstrate left hydronephrosis that gradually worsened in severity as the diuretic took effect. There is no dilatation of the ureter distal to the ureteropelvic junction (arrow).
Fig 2
Ultimately, a diagnosis of Dietl crisis was made and the patient underwent robotic-assisted laparoscopic left pyeloplasty with anterograde insertion of a double-J stent. Subsequently, clinical symptoms did not recur, and follow-up US at 3 months post-operative showed complete resolution of left hydronephrosis.
Discussion
Intermittent abdominal pain is a common complaint in the pediatric population, carrying a wide differential, including Dietl crisis. US is the first-line modality in the uroradiology work up of pediatric hydronephrosis, allowing real-time assessment of the bladder, perivesicular region, ureteral and pelvicalyceal system, as well as the renal parenchymal and reproductive organs [7]. Doppler US can be used to assess renal perfusion and to detect urine jets at the ureterovesicular junction. However, US is limited in its ability to confirm the presence or absence of UPJ obstruction, and a functional modality is often needed.
Functional assessment for urinary obstruction is typically performed with 99mTc-MAG3 diuretic renography, which similar to MRU, includes intravenous pre-hydration and furosemide. The relatively low spatial resolution and exclusive use of planar (ie, nontomographic) images limit the utility of 99mTc-MAG3 diuretic renography in suspected intermittent UPJ obstruction. For example, gradual increase in the severity of hydronephrosis may not be apparent. Time-activity curves are used to quantitate differential renal function, time to peak activity, and urinary drainage. In UPJ obstruction, the affected kidney can demonstrate diminished differential renal function, and prolongation of both time-to-peak activity and urinary drainage half-time. In Dietl's crisis, however, the intermittent nature of symptoms can result in inconclusive or even normal diuretic renography results, commonly necessitating repeat diuretic renography. Renal parenchymal volume and function may be underestimated by planar scintigraphy due to attenuation of radiation by the dilated collecting system. Furthermore, the low spatial resolution of scintigraphy may not be adequate to detect radiotracer in a nondilated ureter.
MRU has emerged as an important advanced imaging modality, allowing both morphological and functional evaluation of the pediatric urinary tract with high spatial resolution and without exposure to ionizing radiation [5]. It is a valuable tool in assessing possible UPJ obstruction, such as in Dietl crisis. Precontrast T2-weighted sequences of urine (MR hydrography) provide detailed visualization of a dilated or nondilated urinary collecting system. Dynamic contrast-enhanced T1-weighted images provide additional structural evaluation of the urinary collecting system and allow for functional analysis including DRF [5]. The most common cause of UPJ obstruction is primary congenital narrowing, but extrinsic compression from an aberrant blood vessel is also common, appearing as flow voids on T2-weighted images [5]. Dynamic contrast-enhanced imaging can distinguish between arterial versus venous structures. The presence of an aberrant blood vessel may or may not alter the surgical approach of the pediatric urologist. In the case presented here, no extrinsic abnormality was visualized, and obstruction was most likely caused by an intrinsic anatomic abnormality at the UPJ that became accentuated with a full renal pelvis, for example stenosis, kinking, or a combination of the two.
Moreover, functional analysis of MRU can be performed using the freely available CHOP-fMRU software. It allows the generation of postcontrast time-intensity curves for the aorta (arterial input function) and for each kidney. In cases of decompensated hydronephrosis, the affected kidney shows delayed TTP, as well as slow washout of parenchymal signal intensity. In this case, TTP was delayed on the left and normal on the right (Fig. 3). Furthermore, the CHOP-fMRU software allows the generation of excretion curves showing the change in relative signal intensity in the renal pelvis over time [6]. In this case, there is delayed excretion into the left renal pelvis, while excretion on the right is normal (Fig. 4). These delayed values, in combination with the delayed CTT and RTT are suggestive of a decompensated hydronephrosis in which the renal parenchymal function is compromised.Fig. 3 Plot demonstrating enhancement over time of the aorta (red), right kidney (blue), and left kidney (green). Time-to-peak (TTP) enhancement was delayed in the left kidney and normal in the right.
Fig 3Fig. 4 Enhancement over time in the right renal pelvis (blue dashed line), and left renal pelvis (green dashed line), superimposed on the plot shown in Fig. 3. There is delayed excretion into the left renal pelvis, while excretion on the right is normal.
Fig 4
Functional analysis allows the calculation of DRF using three different methods, based on: (1) volume of enhancing renal parenchyma (vDRF), (2) glomerular filtration rate (GFR) based on Patlak calculation (pDRF), and (3) combination of vDRF and pDRF (vpDRF) [7]. The pDRF method is based on a Patlak plot showing kidney/aortic intensities as a function of Patlak time (obtained through mathematical transformation of aortic signal intensity), with the slope of each curve representing the GFR index or Patlak number (Fig. 5) [6]. The estimated GFR (eGFR in mL/min) for a unilateral kidney is calculated by multiplying its Patlak number ([mL/min]/mL) by its renal parenchymal volume (mL). In compensated hydronephrosis, renal parenchymal function is typically preserved and pDRF is symmetric; as such, GFR and serum creatinine usually remain within normal levels. The difference between the vDRF and pDRF for each kidney is normally less than 4%. A difference ≥4% in combination with other abnormal MRU parameters suggests decompensated hydronephrosis.Fig. 5 Patlak plot showing kidney/aortic intensities as a function of Patlak time, with the initial slope of each curve representing the GFR index or Patlak number (right kidney in blue; left kidney in green). The Patlak number is expressed in units of (mL/min)/mL.
Fig 5
In our patient, MRU functional analysis demonstrated decompensated left hydronephrosis. The difference between the vDRF and pDRF (≥4%) as well as the delayed CTT, RTT, TTP, and excretion curve are suggestive of decompensated hydronephrosis. Moreover, serum creatinine was found to be normal (Cr = 0.48 mg/dL) while eGFR was 73.11 mL/min when calculated using the above formula, which borders on the normal cut-off of 75 mL/min suggested by Pottel et al. [8]. We hypothesize that MRU can potentially detect unilaterally decreased renal function that would otherwise not be suggested by measured serum Cr level and eGFR. As such, MRU can detect irreversible renal damage, namely tubulointerstitial fibrosis, caused by an intermittent pathologic state such as the episodic UPJ obstruction that occurs in Dietl's crisis.
For long-term follow-up, US is used postoperatively to re-assess the urinary collecting system. MRU may be repeated when it is necessary to evaluate postsurgical anatomy or in the case of recurrent symptoms.
Conclusion
Establishing a diagnosis of Dietl crisis in the pediatric population can be challenging, as it mimics a wide differential of pathologies. US is typically the first-line imaging modality in the acute setting and depending on the timing of the scan, may or may not reveal hydronephrosis in the affected kidney. MRU is a powerful imaging tool that provides both detailed structural information and quantitative functional assessment of a dilated urinary collecting system, leading to greater confidence when considering the diagnosis of Dietl crisis. Confirming diagnosis is crucial as surgical pyeloplasty typically provides complete symptomatic resolution. In our patient, the real-time observation of worsening diuresis-induced hydronephrosis in combination with decompensated MRU parameters are unusual findings that may be unique to Dietl crisis and warrant future research.
Availability of data and material
The reported material is available.
Code availability
Not applicable.
Authors' contributions
Rita Maria Lahoud: manuscript writing and editing. William Esker: data analysis, figure preparation and manuscript editing. Shirley A. Thurston: data analysis, figure preparation and manuscript editing. Jack Elder: manuscript writing and editing. Ruth Lim: manuscript writing and editing, figure preparation.
Ethics approval
Not applicable (case report).
Consent to participate
Not applicable.
Consent for publication
Obtained.
Funding: None.
Competing Interest: The authors have nothing to disclose. | Recovered | ReactionOutcome | CC BY-NC-ND | 33384756 | 18,925,742 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arterial injury'. | Delayed lower extremity paresis following iliosacral screws: Atypical complication and treatment.
Percutaneous iliosacral screw placement has become the technique of choice for treating injuries to the posterior pelvis. However, the technique requires an understanding of the anatomy surrounding the bone corridors to avoid complications and detect them early if they occur. We present the clinical case of a patient with a U-shaped fracture of the sacrum that evolves with gluteal pain and left foot equine paresis after percutaneous fixation with iliosacral screws. Angio-CT of the pelvis shows active arterial bleeding from the superior gluteal artery associated to extensive hematoma in the thickness of the gluteus medius muscle. Emergency embolization is performed by installing coil and gelatin. Successful control of bleeding is achieved. To avoid this complication, a complete imaging study is recommended in planning the surgery and to avoid multiple repositioning of the guide or screw. Arterial injury should be suspected in case of increasing pain despite analgesia, functional impairment or neurological deficit and the angiographic study and resolution by selective embolization of the bleeding vessels must be performed.
Introduction
Advances in the understanding of the radiological anatomy of the pelvis and its bone corridors have allowed a better quality and safety of the osteosynthesis of these fractures [1]. Percutaneous iliosacral screw placement, either supine or prone, has become the technique of choice for treating injuries to the posterior pelvis. However, the percutaneous technique of screw placement requires an understanding of the anatomy surrounding bone corridors, to avoid complications and detect them early if they occur.
As the percutaneous technique is guided by intraoperative X-rays [2], there is no control under direct vision of the neurovascular structures near the entry point. The entry point of the iliosacral screws is close to the sciatic notch, through which the gluteal artery and nerves emerge [3,4]. There are reports of isolated cases of injury to the superior gluteal artery during the placement of percutaneous iliosacral screws [5]. Although rare, the index of suspicion must be high since they are potentially catastrophic.
We present the clinical report of a patient with a U-shaped sacral fracture that evolves with gluteal pain and left foot equine paresis 17 h after percutaneous fixation with iliosacral screws.
Case
An 83-year-old female patient, self-reliant, with a history of atrial fibrillation treated with oral anticoagulant (apixaban), hypothyroidism, lymphroproliferative syndrome, and renal failure.
She suffers a fall at home, impacting in a semi-sitting position. At emergency room the patient shows groin and left buttock pain (VAS 10/10). Physical examination highlights pain on sacral palpation without irradiation, with a normal neurological examination. The imaging study on admission is compatible with left ilium and ischiopubic ramus fractures plus incomplete ipsilateral sacral aileron fracture, without major displacement (Fig. 1a). Orthopedic management is indicated with rest and weight bearing as tolerated with a walker, being discharged on the fifth day of hospitalization.Fig. 1 a) X-ray at first admission, b) X-ray at second admission due persistent pain, c–d) CT shows U-shaped sacrum fracture.
Fig. 1
On the eleventh day after trauma, she returned to the emergency department for hypertensive crisis caused by severe pain in the inguinal region and left buttock, she did not tolerate rehabilitation, sitting or standing.
An X-ray was performed showing displacement of the pelvic fracture (Fig. 1b). The CT-scan shows a complete fracture in the right and left sacral aileron, with displacement. In sagittal view, the sacrum shows kyphosis with an image of a fracture in the coronal plane along the body of S2, configuring a U-shaped fracture of the sacrum (Fig. 1c and d).
The patient underwent reduction and percutaneous osteosynthesis of the iliopubic ramus with supraacetabular and distractor tutor assistance. Subsequently, percutaneous reduction and osteosynthesis of the sacrum was performed with a transiliac-transsacral screw and a iliosacral screw, both from the left side of the pelvis. Intraoperative imaging control was performed with O-arm® that confirms adequate reduction and position of the osteosynthesis. Direct closure of the skin with Ethilon® 3-0.
At recovery room, the patient progresses without pain and with a normal neurovascular status.
10 h postoperatively, the patient begins left gluteal pain, with the neurovascular status intact but with 10% drop in hematocrit. 17 h postoperatively, the patient evolved with an increase in left buttock volume and paresis in the left L5 territory (muscle strength 1/5 in the peroneal muscles and muscular strength 2/5 in the extensor hallucis longus muscle). The dressings at the operative site showed no evidence of bleeding.
Given the suspicion of hematoma, pelvic angiography was performed, showing an image compatible with active arterial bleeding from the superior gluteal artery associated with extensive hematoma in the thickness of the gluteus medius muscle to distal (Fig. 2a and b).Fig. 2 a–b) Pelvic angiography shows active arterial bleeding from the superior gluteal artery associated with extensive hematoma in the thickness of the gluteus medius muscle, c–d) Embolization performed installing coil and gelatin achieving bleeding control.
Fig. 2
Emergency embolization is performed by an interventional radiologist, installing coil and gelatin. Successful control of bleeding is achieved (Fig. 2c and d).
Patient evolves with immediate pain reduction and clinical neurological recovery 1 h post-embolization. Progressively achieves sitting without pain, discharging on the fifth day after embolization.
During the follow-up, the patient progressively returns to her daily self-reliant activities, the last X-ray at 12 months follow-up shows bone healing and minimal displacement of superior pubic ramus screw (Fig. 3).Fig. 3 a) X-ray day after surgery, b) X-ray at 12 months follow-up.
Fig. 3
Discussion
Fragility fractures of the pelvis are injuries seen more frequently today due to the aging of the world population [6]. These injuries have been associated with significant morbidity: chronic pain, loss of independence, need for home hospitalization, prostration, delirium, pneumonia, thromboembolic events, pressure ulcers and urinary complications, among others. In general, the treatment is initially conservative, but an important group of patients do not achieve adequate pain management with these measures.
Among all pelvic insufficiency fractures, a complex group to manage are U-shaped sacrum fractures. They are infrequent fractures and difficult to diagnose, especially if this clinical entity is not known and is not suspected. U-sacrum fractures are generally uncommon injuries, but they are the most common type of spinopelvic dissociation. The U-pattern, which includes vertical fractures on both sacral ala and a transverse fracture on the sacrum, dissociates the pelvic from the spine. In elderly patients, or with osteoporotic bone, U-shaped fractures can be caused by low-energy trauma (falls or even without known trauma), being difficult to investigate with radiographs, even with computed tomography in some cases [7].
An early fixation of this type of fracture prevents displacement, the recurrence of pain and restores the patient's functionality. Percutaneous fixation is one of the most widely used techniques since it minimizes bleeding, operative/anesthetic time, wound complications and confers better recovery rates [1].
Superior gluteal artery injury has a published incidence of 0.6–1.2% in cadaveric studies [4]. Injuries of this type can be caused by direct damage with the insertion of the guide, by tearing the guide, or by direct damage with the placement of the screw. The incidence study is limited given the nature of the soft tissues in cadavers, which are more rigid, and may even have a higher rate compared to living bodies. There are no studies reporting the incidence of superior gluteal artery injury in living patients. This is the only arterial injury diagnosed in the series of 428 percutaneous screws by the main author, equivalent to 0.2%.
Risk factors for superior gluteal artery injury are a history of use of anticoagulants, arterial calcifications, deep anatomical variation of the superior gluteal artery, being closely related to the bone corridor, multiple repositioning of the guide or screw to achieve reduction [8]. This surgical technique should be performed by experienced surgeons to avoid multiple changes at the entry point.
Maslow [9] reported that the combination of the S1 iliosacral screw plus the S2 transsacral-transiliac screw would be safer than the placement of two S1 transsacral-transiliac screws, in relation to the risk of vascular injury to superior gluteal artery. However, it should be mentioned that the fixation used depends on the characteristics of the bone corridors of each patient.
In our patient, it was not possible to determine the exact moment when the injury was done, since there was no evidence of profuse bleeding intraoperatively, and during the first postoperative hours the patient was asymptomatic. It is important to highlight that the screw position was considered correct on fluoroscopy, also verified with intraoperative tomography.
The alternatives reported for the treatment of this injury are performing a tamponade with gauze or extending the incision for exposure and ligation of the artery, which is difficult and not without complications. For this reason, we believe that embolization is the best alternative to stop bleeding previously confirmed by angiography [10].
To avoid this complication, a complete imaging study is recommended to plan the intervention and avoid multiple repositioning of the guide or screw. Arterial injury should be suspected due to profuse bleeding, increasing pain despite analgesia, functional impairment or neurological status deficit. In that case, an angiographic study and resolution using selective embolization of the bleeding vessels must be performed. The clinical manifestation of bleeding and bruising may occur, as in this case, delayed.
In conclusion, a case of superior gluteal artery injury associated to neurological deficit due an extensive hematoma and its successful resolution through embolization, has been reported in a patient with a U fracture of the sacrum fixated with iliosacral screws and transiliac - transsacral screws. | APIXABAN | DrugsGivenReaction | CC BY-NC-ND | 33385056 | 18,943,965 | 2021-02 |
What was the administration route of drug 'APIXABAN'? | Delayed lower extremity paresis following iliosacral screws: Atypical complication and treatment.
Percutaneous iliosacral screw placement has become the technique of choice for treating injuries to the posterior pelvis. However, the technique requires an understanding of the anatomy surrounding the bone corridors to avoid complications and detect them early if they occur. We present the clinical case of a patient with a U-shaped fracture of the sacrum that evolves with gluteal pain and left foot equine paresis after percutaneous fixation with iliosacral screws. Angio-CT of the pelvis shows active arterial bleeding from the superior gluteal artery associated to extensive hematoma in the thickness of the gluteus medius muscle. Emergency embolization is performed by installing coil and gelatin. Successful control of bleeding is achieved. To avoid this complication, a complete imaging study is recommended in planning the surgery and to avoid multiple repositioning of the guide or screw. Arterial injury should be suspected in case of increasing pain despite analgesia, functional impairment or neurological deficit and the angiographic study and resolution by selective embolization of the bleeding vessels must be performed.
Introduction
Advances in the understanding of the radiological anatomy of the pelvis and its bone corridors have allowed a better quality and safety of the osteosynthesis of these fractures [1]. Percutaneous iliosacral screw placement, either supine or prone, has become the technique of choice for treating injuries to the posterior pelvis. However, the percutaneous technique of screw placement requires an understanding of the anatomy surrounding bone corridors, to avoid complications and detect them early if they occur.
As the percutaneous technique is guided by intraoperative X-rays [2], there is no control under direct vision of the neurovascular structures near the entry point. The entry point of the iliosacral screws is close to the sciatic notch, through which the gluteal artery and nerves emerge [3,4]. There are reports of isolated cases of injury to the superior gluteal artery during the placement of percutaneous iliosacral screws [5]. Although rare, the index of suspicion must be high since they are potentially catastrophic.
We present the clinical report of a patient with a U-shaped sacral fracture that evolves with gluteal pain and left foot equine paresis 17 h after percutaneous fixation with iliosacral screws.
Case
An 83-year-old female patient, self-reliant, with a history of atrial fibrillation treated with oral anticoagulant (apixaban), hypothyroidism, lymphroproliferative syndrome, and renal failure.
She suffers a fall at home, impacting in a semi-sitting position. At emergency room the patient shows groin and left buttock pain (VAS 10/10). Physical examination highlights pain on sacral palpation without irradiation, with a normal neurological examination. The imaging study on admission is compatible with left ilium and ischiopubic ramus fractures plus incomplete ipsilateral sacral aileron fracture, without major displacement (Fig. 1a). Orthopedic management is indicated with rest and weight bearing as tolerated with a walker, being discharged on the fifth day of hospitalization.Fig. 1 a) X-ray at first admission, b) X-ray at second admission due persistent pain, c–d) CT shows U-shaped sacrum fracture.
Fig. 1
On the eleventh day after trauma, she returned to the emergency department for hypertensive crisis caused by severe pain in the inguinal region and left buttock, she did not tolerate rehabilitation, sitting or standing.
An X-ray was performed showing displacement of the pelvic fracture (Fig. 1b). The CT-scan shows a complete fracture in the right and left sacral aileron, with displacement. In sagittal view, the sacrum shows kyphosis with an image of a fracture in the coronal plane along the body of S2, configuring a U-shaped fracture of the sacrum (Fig. 1c and d).
The patient underwent reduction and percutaneous osteosynthesis of the iliopubic ramus with supraacetabular and distractor tutor assistance. Subsequently, percutaneous reduction and osteosynthesis of the sacrum was performed with a transiliac-transsacral screw and a iliosacral screw, both from the left side of the pelvis. Intraoperative imaging control was performed with O-arm® that confirms adequate reduction and position of the osteosynthesis. Direct closure of the skin with Ethilon® 3-0.
At recovery room, the patient progresses without pain and with a normal neurovascular status.
10 h postoperatively, the patient begins left gluteal pain, with the neurovascular status intact but with 10% drop in hematocrit. 17 h postoperatively, the patient evolved with an increase in left buttock volume and paresis in the left L5 territory (muscle strength 1/5 in the peroneal muscles and muscular strength 2/5 in the extensor hallucis longus muscle). The dressings at the operative site showed no evidence of bleeding.
Given the suspicion of hematoma, pelvic angiography was performed, showing an image compatible with active arterial bleeding from the superior gluteal artery associated with extensive hematoma in the thickness of the gluteus medius muscle to distal (Fig. 2a and b).Fig. 2 a–b) Pelvic angiography shows active arterial bleeding from the superior gluteal artery associated with extensive hematoma in the thickness of the gluteus medius muscle, c–d) Embolization performed installing coil and gelatin achieving bleeding control.
Fig. 2
Emergency embolization is performed by an interventional radiologist, installing coil and gelatin. Successful control of bleeding is achieved (Fig. 2c and d).
Patient evolves with immediate pain reduction and clinical neurological recovery 1 h post-embolization. Progressively achieves sitting without pain, discharging on the fifth day after embolization.
During the follow-up, the patient progressively returns to her daily self-reliant activities, the last X-ray at 12 months follow-up shows bone healing and minimal displacement of superior pubic ramus screw (Fig. 3).Fig. 3 a) X-ray day after surgery, b) X-ray at 12 months follow-up.
Fig. 3
Discussion
Fragility fractures of the pelvis are injuries seen more frequently today due to the aging of the world population [6]. These injuries have been associated with significant morbidity: chronic pain, loss of independence, need for home hospitalization, prostration, delirium, pneumonia, thromboembolic events, pressure ulcers and urinary complications, among others. In general, the treatment is initially conservative, but an important group of patients do not achieve adequate pain management with these measures.
Among all pelvic insufficiency fractures, a complex group to manage are U-shaped sacrum fractures. They are infrequent fractures and difficult to diagnose, especially if this clinical entity is not known and is not suspected. U-sacrum fractures are generally uncommon injuries, but they are the most common type of spinopelvic dissociation. The U-pattern, which includes vertical fractures on both sacral ala and a transverse fracture on the sacrum, dissociates the pelvic from the spine. In elderly patients, or with osteoporotic bone, U-shaped fractures can be caused by low-energy trauma (falls or even without known trauma), being difficult to investigate with radiographs, even with computed tomography in some cases [7].
An early fixation of this type of fracture prevents displacement, the recurrence of pain and restores the patient's functionality. Percutaneous fixation is one of the most widely used techniques since it minimizes bleeding, operative/anesthetic time, wound complications and confers better recovery rates [1].
Superior gluteal artery injury has a published incidence of 0.6–1.2% in cadaveric studies [4]. Injuries of this type can be caused by direct damage with the insertion of the guide, by tearing the guide, or by direct damage with the placement of the screw. The incidence study is limited given the nature of the soft tissues in cadavers, which are more rigid, and may even have a higher rate compared to living bodies. There are no studies reporting the incidence of superior gluteal artery injury in living patients. This is the only arterial injury diagnosed in the series of 428 percutaneous screws by the main author, equivalent to 0.2%.
Risk factors for superior gluteal artery injury are a history of use of anticoagulants, arterial calcifications, deep anatomical variation of the superior gluteal artery, being closely related to the bone corridor, multiple repositioning of the guide or screw to achieve reduction [8]. This surgical technique should be performed by experienced surgeons to avoid multiple changes at the entry point.
Maslow [9] reported that the combination of the S1 iliosacral screw plus the S2 transsacral-transiliac screw would be safer than the placement of two S1 transsacral-transiliac screws, in relation to the risk of vascular injury to superior gluteal artery. However, it should be mentioned that the fixation used depends on the characteristics of the bone corridors of each patient.
In our patient, it was not possible to determine the exact moment when the injury was done, since there was no evidence of profuse bleeding intraoperatively, and during the first postoperative hours the patient was asymptomatic. It is important to highlight that the screw position was considered correct on fluoroscopy, also verified with intraoperative tomography.
The alternatives reported for the treatment of this injury are performing a tamponade with gauze or extending the incision for exposure and ligation of the artery, which is difficult and not without complications. For this reason, we believe that embolization is the best alternative to stop bleeding previously confirmed by angiography [10].
To avoid this complication, a complete imaging study is recommended to plan the intervention and avoid multiple repositioning of the guide or screw. Arterial injury should be suspected due to profuse bleeding, increasing pain despite analgesia, functional impairment or neurological status deficit. In that case, an angiographic study and resolution using selective embolization of the bleeding vessels must be performed. The clinical manifestation of bleeding and bruising may occur, as in this case, delayed.
In conclusion, a case of superior gluteal artery injury associated to neurological deficit due an extensive hematoma and its successful resolution through embolization, has been reported in a patient with a U fracture of the sacrum fixated with iliosacral screws and transiliac - transsacral screws. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33385056 | 18,943,965 | 2021-02 |
What was the outcome of reaction 'Arterial injury'? | Delayed lower extremity paresis following iliosacral screws: Atypical complication and treatment.
Percutaneous iliosacral screw placement has become the technique of choice for treating injuries to the posterior pelvis. However, the technique requires an understanding of the anatomy surrounding the bone corridors to avoid complications and detect them early if they occur. We present the clinical case of a patient with a U-shaped fracture of the sacrum that evolves with gluteal pain and left foot equine paresis after percutaneous fixation with iliosacral screws. Angio-CT of the pelvis shows active arterial bleeding from the superior gluteal artery associated to extensive hematoma in the thickness of the gluteus medius muscle. Emergency embolization is performed by installing coil and gelatin. Successful control of bleeding is achieved. To avoid this complication, a complete imaging study is recommended in planning the surgery and to avoid multiple repositioning of the guide or screw. Arterial injury should be suspected in case of increasing pain despite analgesia, functional impairment or neurological deficit and the angiographic study and resolution by selective embolization of the bleeding vessels must be performed.
Introduction
Advances in the understanding of the radiological anatomy of the pelvis and its bone corridors have allowed a better quality and safety of the osteosynthesis of these fractures [1]. Percutaneous iliosacral screw placement, either supine or prone, has become the technique of choice for treating injuries to the posterior pelvis. However, the percutaneous technique of screw placement requires an understanding of the anatomy surrounding bone corridors, to avoid complications and detect them early if they occur.
As the percutaneous technique is guided by intraoperative X-rays [2], there is no control under direct vision of the neurovascular structures near the entry point. The entry point of the iliosacral screws is close to the sciatic notch, through which the gluteal artery and nerves emerge [3,4]. There are reports of isolated cases of injury to the superior gluteal artery during the placement of percutaneous iliosacral screws [5]. Although rare, the index of suspicion must be high since they are potentially catastrophic.
We present the clinical report of a patient with a U-shaped sacral fracture that evolves with gluteal pain and left foot equine paresis 17 h after percutaneous fixation with iliosacral screws.
Case
An 83-year-old female patient, self-reliant, with a history of atrial fibrillation treated with oral anticoagulant (apixaban), hypothyroidism, lymphroproliferative syndrome, and renal failure.
She suffers a fall at home, impacting in a semi-sitting position. At emergency room the patient shows groin and left buttock pain (VAS 10/10). Physical examination highlights pain on sacral palpation without irradiation, with a normal neurological examination. The imaging study on admission is compatible with left ilium and ischiopubic ramus fractures plus incomplete ipsilateral sacral aileron fracture, without major displacement (Fig. 1a). Orthopedic management is indicated with rest and weight bearing as tolerated with a walker, being discharged on the fifth day of hospitalization.Fig. 1 a) X-ray at first admission, b) X-ray at second admission due persistent pain, c–d) CT shows U-shaped sacrum fracture.
Fig. 1
On the eleventh day after trauma, she returned to the emergency department for hypertensive crisis caused by severe pain in the inguinal region and left buttock, she did not tolerate rehabilitation, sitting or standing.
An X-ray was performed showing displacement of the pelvic fracture (Fig. 1b). The CT-scan shows a complete fracture in the right and left sacral aileron, with displacement. In sagittal view, the sacrum shows kyphosis with an image of a fracture in the coronal plane along the body of S2, configuring a U-shaped fracture of the sacrum (Fig. 1c and d).
The patient underwent reduction and percutaneous osteosynthesis of the iliopubic ramus with supraacetabular and distractor tutor assistance. Subsequently, percutaneous reduction and osteosynthesis of the sacrum was performed with a transiliac-transsacral screw and a iliosacral screw, both from the left side of the pelvis. Intraoperative imaging control was performed with O-arm® that confirms adequate reduction and position of the osteosynthesis. Direct closure of the skin with Ethilon® 3-0.
At recovery room, the patient progresses without pain and with a normal neurovascular status.
10 h postoperatively, the patient begins left gluteal pain, with the neurovascular status intact but with 10% drop in hematocrit. 17 h postoperatively, the patient evolved with an increase in left buttock volume and paresis in the left L5 territory (muscle strength 1/5 in the peroneal muscles and muscular strength 2/5 in the extensor hallucis longus muscle). The dressings at the operative site showed no evidence of bleeding.
Given the suspicion of hematoma, pelvic angiography was performed, showing an image compatible with active arterial bleeding from the superior gluteal artery associated with extensive hematoma in the thickness of the gluteus medius muscle to distal (Fig. 2a and b).Fig. 2 a–b) Pelvic angiography shows active arterial bleeding from the superior gluteal artery associated with extensive hematoma in the thickness of the gluteus medius muscle, c–d) Embolization performed installing coil and gelatin achieving bleeding control.
Fig. 2
Emergency embolization is performed by an interventional radiologist, installing coil and gelatin. Successful control of bleeding is achieved (Fig. 2c and d).
Patient evolves with immediate pain reduction and clinical neurological recovery 1 h post-embolization. Progressively achieves sitting without pain, discharging on the fifth day after embolization.
During the follow-up, the patient progressively returns to her daily self-reliant activities, the last X-ray at 12 months follow-up shows bone healing and minimal displacement of superior pubic ramus screw (Fig. 3).Fig. 3 a) X-ray day after surgery, b) X-ray at 12 months follow-up.
Fig. 3
Discussion
Fragility fractures of the pelvis are injuries seen more frequently today due to the aging of the world population [6]. These injuries have been associated with significant morbidity: chronic pain, loss of independence, need for home hospitalization, prostration, delirium, pneumonia, thromboembolic events, pressure ulcers and urinary complications, among others. In general, the treatment is initially conservative, but an important group of patients do not achieve adequate pain management with these measures.
Among all pelvic insufficiency fractures, a complex group to manage are U-shaped sacrum fractures. They are infrequent fractures and difficult to diagnose, especially if this clinical entity is not known and is not suspected. U-sacrum fractures are generally uncommon injuries, but they are the most common type of spinopelvic dissociation. The U-pattern, which includes vertical fractures on both sacral ala and a transverse fracture on the sacrum, dissociates the pelvic from the spine. In elderly patients, or with osteoporotic bone, U-shaped fractures can be caused by low-energy trauma (falls or even without known trauma), being difficult to investigate with radiographs, even with computed tomography in some cases [7].
An early fixation of this type of fracture prevents displacement, the recurrence of pain and restores the patient's functionality. Percutaneous fixation is one of the most widely used techniques since it minimizes bleeding, operative/anesthetic time, wound complications and confers better recovery rates [1].
Superior gluteal artery injury has a published incidence of 0.6–1.2% in cadaveric studies [4]. Injuries of this type can be caused by direct damage with the insertion of the guide, by tearing the guide, or by direct damage with the placement of the screw. The incidence study is limited given the nature of the soft tissues in cadavers, which are more rigid, and may even have a higher rate compared to living bodies. There are no studies reporting the incidence of superior gluteal artery injury in living patients. This is the only arterial injury diagnosed in the series of 428 percutaneous screws by the main author, equivalent to 0.2%.
Risk factors for superior gluteal artery injury are a history of use of anticoagulants, arterial calcifications, deep anatomical variation of the superior gluteal artery, being closely related to the bone corridor, multiple repositioning of the guide or screw to achieve reduction [8]. This surgical technique should be performed by experienced surgeons to avoid multiple changes at the entry point.
Maslow [9] reported that the combination of the S1 iliosacral screw plus the S2 transsacral-transiliac screw would be safer than the placement of two S1 transsacral-transiliac screws, in relation to the risk of vascular injury to superior gluteal artery. However, it should be mentioned that the fixation used depends on the characteristics of the bone corridors of each patient.
In our patient, it was not possible to determine the exact moment when the injury was done, since there was no evidence of profuse bleeding intraoperatively, and during the first postoperative hours the patient was asymptomatic. It is important to highlight that the screw position was considered correct on fluoroscopy, also verified with intraoperative tomography.
The alternatives reported for the treatment of this injury are performing a tamponade with gauze or extending the incision for exposure and ligation of the artery, which is difficult and not without complications. For this reason, we believe that embolization is the best alternative to stop bleeding previously confirmed by angiography [10].
To avoid this complication, a complete imaging study is recommended to plan the intervention and avoid multiple repositioning of the guide or screw. Arterial injury should be suspected due to profuse bleeding, increasing pain despite analgesia, functional impairment or neurological status deficit. In that case, an angiographic study and resolution using selective embolization of the bleeding vessels must be performed. The clinical manifestation of bleeding and bruising may occur, as in this case, delayed.
In conclusion, a case of superior gluteal artery injury associated to neurological deficit due an extensive hematoma and its successful resolution through embolization, has been reported in a patient with a U fracture of the sacrum fixated with iliosacral screws and transiliac - transsacral screws. | Recovered | ReactionOutcome | CC BY-NC-ND | 33385056 | 18,943,965 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abortion spontaneous'. | Serratia marcescens as a cause of unfavorable outcome in the twin pregnancy.
Several Serratia species are widely distributed in nature, but Serratia marcescens is the only species frequently isolated in hospitals. This pathogen is mainly responsible for nosocomial infection, mostly in immunocompromised hosts. A 26-year-old woman with a twin pregnancy, regularly controlled, was hospitalized at 24 + 5 weeks of gestation due to scant vaginal bleeding, lower abdominal pain, and body temperature up to 37.5°C. Gynecological examination revealed bleeding accompanied by dilatation of the cervix. The laboratory analyses revealed leukocytosis with elevated C-reactive protein (CRP). Treatment was initiated with intravenous antibiotic administration. After admission, fetal membranes spontaneously ruptured, and an extremely preterm dichorionic female twin birth occurred at 25 + 0 weeks of gestation. Both infants died two days after labor. Pathological and microbiological analyses revealed chorioamnionitis caused by S. marcescens. According to the antibiogram, antibiotic treatment was continued for the next 7 days. The examination of cervical and vaginal discharge samples was negative three days and two weeks after therapy. S. marcescens may cause spontaneous miscarriages and, in this important case, caused loss of discordant twins in an extremely preterm birth by an immunocompetent patient. Infection by S. marcescens cannot be excluded as a cause of discordant growth and needs to be confirmed by further research.
1 Introduction
Serratia marcescens is an aerobic (facultative anaerobic), motile, Gram-negative, enteric saprophytic rod of the Klebsiella–Enterobacter–Serratia division of the Enterobacteriaceae family [1]. S. marcescens is observed almost everywhere in nature, but it favors moist conditions [2]. In this paper, a case of S. marcescens placental infection is described as a cause of extremely preterm birth and loss of infants in twin pregnancy due to pneumonitis followed by respiratory insufficiency.
Infections during pregnancy are complex and important because the infection affects not only the mother, but also the fetus [3]. The duration and results of the infection depend on the number and virulence of the microbes, the immunobiological characteristics of the mother, the manner of spread of the infection, and the gestational period [4]. The immunobiological status of the mother is stressed given the depressed T lymphocyte function and frequent compositional alterations in biological flora in the birth canal during pregnancy, which significantly contributes to the development of infections [5].
As a result of infections during pregnancy, fetal membranes may become infected (chorioamnionitis and intraamniotic infection syndrome), resulting in premature placental abruption and spontaneous miscarriage or preterm birth [6]. Due to the very high infant death rate under these conditions, the peripartum morbidity of the mother is also high [7]. In line with these findings, Serratia bacteremia has a high mortality rate of approximately 37% within six months [8]. During pregnancy, this infection is a rare but potentially fatal disorder that is also associated with chorioamnionitis or placental abscess, miscarriages, and preterm deliveries [9,10,11,12,13,14].
2 Case report
A 26-year-old (gravida 2, para 1), Rh-negative, childbearing mother with an Rh-positive partner undergoing a regularly controlled second dichorionic twin pregnancy was the subject of this study. The first pregnancy proceeded normally and yielded a positive outcome. Due to uterine cervical insufficiency during this pregnancy, a cerclage was placed at 15 weeks of gestation (WG). Discordant fetal growth restriction (FGR) was diagnosed by ultrasound at 24 + 3 WG based on an estimated discordance of approximately 25% (ultrasound parameters of the first twin: 61 mm biparietal diameter (BPD), 45 mm femur length (FL), 19.8 cm abdominal circumference (AC), 22.6 cm head circumference (HC), and approximately 530 g estimated fetal weight (EFW); ultrasound parameters of the 2nd twin: 65 mm BPD, 48 mm FL, 21 cm AC, 23.8 cm HC, and approximately 730 g EFW.
The patient was admitted to the hospital at 24 + 5 WG for scant vaginal bleeding, lower abdominal pain, and body temperature up to 37.5°C. Gynecological examination revealed bleeding within dilatation of the cervix with a diameter of 1 cm near the cerclage. The laboratory analyses revealed leukocytosis with elevated C-reactive protein (CRP) (28.3 × 109/L white blood cells (WBCs), 3.50 × 109/L red blood cells (RBCs), 108 g/L hemoglobin (Hgb), 385 × 109/L platelet count (PLT), and 28.5 mg/L CRP. Other laboratory analyses were in range with reference values. Treatment was initiated with intravenous administration of ceftriaxone at a dose of 2 g/day. Immediately after admission, fetal membranes spontaneously ruptured, and the mother experienced uterine contractions. The cerclage was removed, and an extremely preterm dichorionic female twin birth with discordant FGR occurred at 25 + 0 WG. The first twin weighed 560 g and had an AS of 2/2, and the second twin weighed 780 g and had an AS of 2/2. Both female infants had an altered state of consciousness and were edematous, hypotonic, apneic, and bradycardic, with multiple hematomas at the extremities and in the occipital region, and had leukocytosis (95.6 × 109/L WBCs in the first and 38.9 × 109/L WBCs in the second newborn). Swabs of the umbilical cord, nose, and anus were negative for both infants. Chest X-ray of the first newborn showed decreased transparency of the pulmonary parenchyma to the left with a clearly limited presence in the upper lobe area to the right (Figure 1a). Radiography of the second infant confirmed individual paracardial and basal shadings of the pulmonary parenchyma (Figure 1b). Ultrasound indicated the immaturity of the brain parenchyma in both newborns with asymmetry of the ventricular system and plexus. Both infants were attached to mechanical ventilation, followed by treatment with electrolytes, a prophylactic dose of corticosteroids, and antibiotic therapy. The infants died two days after birth due to respiratory failure despite resuscitation.
Figure 1 Chest X-ray of the newborns. (a) Image shows decreased transparency of the pulmonary parenchyma to the left with a clearly limited presence in the upper lobe area to the right in the first newborn; (b) chest X-ray shows individual paracardial and basal shadings of the pulmonary parenchyma in the second newborn.
The placental tissue was sent for pathological and microbiological analyses. Pathological examination of placental tissue samples showed marginal hemorrhage and opaque membranes with yellow-green discoloration and purulent amniotic fluid. Microscopic analysis showed neutrophilic infiltrate of membranes and those overlying the chorionic plate with rare macrophages and without necrosis, including umbilical vasculitis. A diagnosis of acute chorioamnionitis was made (Figure 2). According to the Amsterdam consensus criteria for maternal and fetal inflammatory responses, our case was classified as Stage 2, Grade 2 [15]. Tests for the presence of genital mycoplasma (Ureaplasma urealyticum and Mycoplasma hominis) were negative, and real-time polymerase chain reaction (PCR) tests assessing the presence of Neisseria gonorrhoeae and Chlamydia trachomatis were negative. Applying the same examinations, the presence of the bacteria S. marcescens was discovered. Moreover, in a touch preparation of the placental tissue, dead cells were identified (up to 30 leukocytes in the visible range) [16]. After delivery on the third day of hospitalization, treatment was continued with amikacin (1 g/day) and ceftriaxone (2 g/day). On the ninth day of admission, the patient was discharged and treatment was continued according to the antibiogram, with ciprofloxacin at an oral dose of 1 g/day for the next 7 days. Control cervical and vaginal discharge samples were negative three days and two weeks after therapy.
Figure 2 Histological features of chorioamnionitis caused by Serratia marcescens. Photomicrographs of the placental tissue show neutrophilic infiltrate of membranes and those overlying the chorionic plate with rare macrophages and without necrotic debris; (a) hematoxylin and eosin staining, ×200; (b) hematoxylin and eosin staining, ×400; (c) hematoxylin and eosin staining, ×400.
Informed consent: Informed consent has been obtained from a mother for potentially descriptive information to be published in this article.
3 Discussion
According to the available data, an infection caused by S. marcescens results in a miscarriage or extremely preterm birth by an immunocompetent patient, thereby making this case very interesting [13]. Registered in 1960, this bacterial species is often described as a cause of nosocomial interhospital infections [2]. Although this species is sensitive to a wide range of available antibiotics, it is often difficult to exterminate this species from the facilities implicated in interhospital infections [2].
Van Ogtrop et al. followed an outbreak of colonization and infection with S. marcescens that occurred in a neonatal intensive care unit [17]. S. marcescens was isolated from five preterm infants between 25–30 weeks of gestation. Two infants developed fatal septicemia, and one infant experienced conjunctivitis due to S. marcescens [17]. Two infants were colonized, but did not display clinical signs of infection. All infants were treated with antibiotic regimens, including ciprofloxacin and gentamicin [17].
David et al. analyzed twenty-one patients who were infected or colonized in a neonatal unit over a 9-month period from 2001–2002 [18]. Twenty-two isolates were examined for antibiotic susceptibility, β-lactamase production, and genotype [18]. Random-amplified polymorphic deoxyribonucleic acid (DNA) PCR and pulsed-field gel electrophoresis revealed that two clones were present [18]. The first clone caused invasive clinical infection in four babies and was subsequently replaced by a noninvasive clone that affected 14 babies [18]. According to their production of prodigiosin, two different strains have been described: the first strain was nonpigmented, while the second exhibited pink-red pigmentation [18]. The clinical features suggested the difference in the scope of pathogenicities of these two strains. No environmental source was identified [18].
S. marcescens has only recently been implicated as a cause of miscarriages and preterm labor resulting from bacteremia and chorioamnionitis [9,10,12]. Prior rupture of membranes is not necessarily due to the development of an ascending amniotic infection [19]. It has been established that subclinical intrauterine infection may occur, even with intact membranes, leading to the absence of clinical signs of infection, despite clear histological signs of chorioamnionitis [20]. The way the infection occurred and spread in this case is not clear. In some cases, the growth and spread of the infection occurred from the vagina, which was confirmed by a vaginal swab [9,13,14]. S. marcescens is not part of the normal vaginal flora and is most commonly encountered as an opportunistic pathogen in nosocomial settings [21]. It is typically associated with the use of invasive devices or procedures (e.g., chorionic villus sampling, placement of a central venous line), repeated vaginal examinations after preterm prelabor rupture of membranes as well as with patients whose health is generally compromised [9,11,14]. It is also associated with poor hygiene in health care facilities (hands of personnel, contaminated irrigation solutions or disinfectants) and prior unsuccessful antibiotic treatments of patients [22]. In the hospital, Serratia species tend to colonize the respiratory and urinary tracts of adults rather than the gastrointestinal tract (2).
Amniocentesis is very important in the diagnosis of chorioamnionitis. This invasive procedure is followed by risks of miscarriage and transmission of the infection to the fetus [21]. On the other hand, a negative result cannot completely exclude chorioamnionitis, especially at an early stage [11]. In this case, this procedure was not performed. A review of the reported cases of Serratia marcescens chorioamnionitis is presented in Table 1.
Table 1 Review of the reported cases of Serratia marcescens chorioamnionitis
No Reference Year Age WG Immunocompetent host Source of infection Symptoms on admission Outcome Treatment Length of hospitalization
1. Kljakic et al. (Current study) 2020 26 25 Yes Unknown Scant vaginal bleeding, lower abdominal pain, fever Vaginal preterm delivery; Infants died two days after birth. Ceftriaxone (3 days). After delivery, the treatment was continued with Amikacin and Ceftriaxone (6 days) and followed by Ciprofloxacin according to the antibiogram (7 days) 9 days
2. Mak et al. [21] 2018 35 15–37 Yes Ascending infection from the vagina Fever, chills, rigor, runny nose, cough, sputum, headache, myalgia, vomiting undigested food Vaginal term delivery (uninfected newborn) Meropenem 24 weeks
3. Erenberg et al. [14] 2017 36 25–28 Yes Prolonged PPROM Chills, abdominal pain, sub-febrile fever, tachycardia, leukocytosis, fetal tachycardia Emergency cesarean delivery Amoxicillin/Clavulanic Acid (3 days), followed by Meropenem (6 days) 11 days
4. Vale-Fernandes et al. [13] 2015 31 15–16 Yes N/A Hyperthermia, hemicranial headache, nausea, vomiting, diarrhea Spontaneous abortion Ceftriaxone and Ampicillin (12 days), followed by only Ceftriaxone (2 days) 12 days
5. Chai et al. [12] 2011 32 12 No Unknown Amenorrhea, fever, chills, vomiting Fetal death followed by vacuum curettage Meropenem N/A
6. Meirowitz et al. [11] 2006 28 21–25 No Central catheter line Fever, chills, malaise, headache Emergency cesarean delivery Ceftriaxone (11 days), followed by Ertapenem (17 days), followed by Imipenem (14 days) 41 days
7. Shimizu et al. [10] 2003 26 10–20 Yes Urinary tract Gait disturbance, severe tenderness, flaring in the lower left extremity, fever Spontaneous abortion Cefotiam (5 days), followed by Ceftazidime (8 days), followed by Imipenem/Cilastatin (8 days). Second admission – Ceftriaxone and Imipenem/Cilastatin up to the abortion?, followed by Imipenem/Cilastatin (by the 7 day after the abortion 7) 40 days during first admission? Period of the second admission is N/A
8. Prosser et al. [9] 2003 38 19–21 Yes Chorionic-villus sampling Intermittent fevers, malaise. Spontaneous abortion Tobramycin and Cefepime (12 days) followed by Trimethoprim–sulfamethoxazole and Cefepime (2 weeks?) 12 days
Potentially, two mechanisms of fetal loss are associated with infection, and both are characteristic of advanced pregnancy. First, bacterial invasion of the amniotic cavity or fetoplacental membranes can stimulate labor of an immature fetus, and second, intrauterine infection of the fetus can probably occur as a result of the swallowing or inhaling of infected amniotic fluid and cause fetal pneumonitis and/or septicemia [20].
FGR is defined as a condition in which the fetus does not achieve its genetically determined growth potential [23]. FGR can be caused by a variety of factors, such as infections, the mother’s illnesses, and chromosomal disorders, but it primarily refers to anomalies in placental development that occur early in pregnancy [24,25]. The pathophysiology of discordant FGR remains insufficiently and inaccurately defined. Several recognized factors, categorized as maternal, fetal, and placental, influence the likelihood of discordant twins [26]. Altogether, with factors including intrauterine surroundings and utero-placental insufficiency, this condition can lead to discordant FGR [26].
Discordant fetal growth (with greater than 20% discordance) complicates 15% to 29% of twin pregnancies [27]. In a study involving 15,066 twin pregnancies, the rate of miscarriage was significantly increased when discordance was greater than 20%, especially in cases of monochorionic twin pregnancies [28]. It is important to note that the pregnancy in this case report was dichorionic. The increased pregnancy loss rate is attributed to monochorionicity of twin pregnancy [29].
In this case, infection by S. marcescens cannot be excluded as a cause of discordant growth. This is supported by the lack of awareness of the pregnancy period when the infection occurred. Previous studies have shown that chronic chorioamnionitis in some cases may be the cause of restrictive intrauterine growth of the fetus, especially in twin pregnancies [30]. Thus, it is reported, on rare occasions, that bacterial infections such as chlamydia, mycoplasma, listeria, and tuberculosis can cause restrictive intrauterine growth [31]. In addition, studies are required to examine the association between localization and/or different bacterial populations with the degree of oxygenation and maternal and fetal circulation. The immunomodulatory effect caused by bacterial infections of the placenta, hypothetically, may be the reason for the restrictive growth of the fetus and its subsequent rejection or preterm birth, and this needs to be confirmed by further research.
4 Conclusions
Although rare, S. marcescens can cause spontaneous miscarriages and, in this case, loss of extremely preterm birth of discordant twins in an immunocompetent patient. Infection by S. marcescens cannot be excluded as a cause of discordant growth and needs to be confirmed by further research.
Abbreviations
ACabdominal circumference
BPDbiparietal diameter
CRPC-reactive protein
DNAdeoxyribonucleic acid
EFWestimated fetal weight
FGRfetal growth restriction
FLfemur length
HChead circumference
Hgbhemoglobin
PCRpolymerase chain reaction
PLTplatelet count
RBCsred blood cells
WBCswhite blood cells
WGweeks of gestation
Acknowledgments
We would like to express special gratitude to our friend and colleague Duško Kljakić who died during the Covid 19 epidemic.
Conflict of interest: Authors state no conflict of interest.
Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | AMPICILLIN, CEFTRIAXONE | DrugsGivenReaction | CC BY | 33385065 | 19,704,876 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Serratia marcescens as a cause of unfavorable outcome in the twin pregnancy.
Several Serratia species are widely distributed in nature, but Serratia marcescens is the only species frequently isolated in hospitals. This pathogen is mainly responsible for nosocomial infection, mostly in immunocompromised hosts. A 26-year-old woman with a twin pregnancy, regularly controlled, was hospitalized at 24 + 5 weeks of gestation due to scant vaginal bleeding, lower abdominal pain, and body temperature up to 37.5°C. Gynecological examination revealed bleeding accompanied by dilatation of the cervix. The laboratory analyses revealed leukocytosis with elevated C-reactive protein (CRP). Treatment was initiated with intravenous antibiotic administration. After admission, fetal membranes spontaneously ruptured, and an extremely preterm dichorionic female twin birth occurred at 25 + 0 weeks of gestation. Both infants died two days after labor. Pathological and microbiological analyses revealed chorioamnionitis caused by S. marcescens. According to the antibiogram, antibiotic treatment was continued for the next 7 days. The examination of cervical and vaginal discharge samples was negative three days and two weeks after therapy. S. marcescens may cause spontaneous miscarriages and, in this important case, caused loss of discordant twins in an extremely preterm birth by an immunocompetent patient. Infection by S. marcescens cannot be excluded as a cause of discordant growth and needs to be confirmed by further research.
1 Introduction
Serratia marcescens is an aerobic (facultative anaerobic), motile, Gram-negative, enteric saprophytic rod of the Klebsiella–Enterobacter–Serratia division of the Enterobacteriaceae family [1]. S. marcescens is observed almost everywhere in nature, but it favors moist conditions [2]. In this paper, a case of S. marcescens placental infection is described as a cause of extremely preterm birth and loss of infants in twin pregnancy due to pneumonitis followed by respiratory insufficiency.
Infections during pregnancy are complex and important because the infection affects not only the mother, but also the fetus [3]. The duration and results of the infection depend on the number and virulence of the microbes, the immunobiological characteristics of the mother, the manner of spread of the infection, and the gestational period [4]. The immunobiological status of the mother is stressed given the depressed T lymphocyte function and frequent compositional alterations in biological flora in the birth canal during pregnancy, which significantly contributes to the development of infections [5].
As a result of infections during pregnancy, fetal membranes may become infected (chorioamnionitis and intraamniotic infection syndrome), resulting in premature placental abruption and spontaneous miscarriage or preterm birth [6]. Due to the very high infant death rate under these conditions, the peripartum morbidity of the mother is also high [7]. In line with these findings, Serratia bacteremia has a high mortality rate of approximately 37% within six months [8]. During pregnancy, this infection is a rare but potentially fatal disorder that is also associated with chorioamnionitis or placental abscess, miscarriages, and preterm deliveries [9,10,11,12,13,14].
2 Case report
A 26-year-old (gravida 2, para 1), Rh-negative, childbearing mother with an Rh-positive partner undergoing a regularly controlled second dichorionic twin pregnancy was the subject of this study. The first pregnancy proceeded normally and yielded a positive outcome. Due to uterine cervical insufficiency during this pregnancy, a cerclage was placed at 15 weeks of gestation (WG). Discordant fetal growth restriction (FGR) was diagnosed by ultrasound at 24 + 3 WG based on an estimated discordance of approximately 25% (ultrasound parameters of the first twin: 61 mm biparietal diameter (BPD), 45 mm femur length (FL), 19.8 cm abdominal circumference (AC), 22.6 cm head circumference (HC), and approximately 530 g estimated fetal weight (EFW); ultrasound parameters of the 2nd twin: 65 mm BPD, 48 mm FL, 21 cm AC, 23.8 cm HC, and approximately 730 g EFW.
The patient was admitted to the hospital at 24 + 5 WG for scant vaginal bleeding, lower abdominal pain, and body temperature up to 37.5°C. Gynecological examination revealed bleeding within dilatation of the cervix with a diameter of 1 cm near the cerclage. The laboratory analyses revealed leukocytosis with elevated C-reactive protein (CRP) (28.3 × 109/L white blood cells (WBCs), 3.50 × 109/L red blood cells (RBCs), 108 g/L hemoglobin (Hgb), 385 × 109/L platelet count (PLT), and 28.5 mg/L CRP. Other laboratory analyses were in range with reference values. Treatment was initiated with intravenous administration of ceftriaxone at a dose of 2 g/day. Immediately after admission, fetal membranes spontaneously ruptured, and the mother experienced uterine contractions. The cerclage was removed, and an extremely preterm dichorionic female twin birth with discordant FGR occurred at 25 + 0 WG. The first twin weighed 560 g and had an AS of 2/2, and the second twin weighed 780 g and had an AS of 2/2. Both female infants had an altered state of consciousness and were edematous, hypotonic, apneic, and bradycardic, with multiple hematomas at the extremities and in the occipital region, and had leukocytosis (95.6 × 109/L WBCs in the first and 38.9 × 109/L WBCs in the second newborn). Swabs of the umbilical cord, nose, and anus were negative for both infants. Chest X-ray of the first newborn showed decreased transparency of the pulmonary parenchyma to the left with a clearly limited presence in the upper lobe area to the right (Figure 1a). Radiography of the second infant confirmed individual paracardial and basal shadings of the pulmonary parenchyma (Figure 1b). Ultrasound indicated the immaturity of the brain parenchyma in both newborns with asymmetry of the ventricular system and plexus. Both infants were attached to mechanical ventilation, followed by treatment with electrolytes, a prophylactic dose of corticosteroids, and antibiotic therapy. The infants died two days after birth due to respiratory failure despite resuscitation.
Figure 1 Chest X-ray of the newborns. (a) Image shows decreased transparency of the pulmonary parenchyma to the left with a clearly limited presence in the upper lobe area to the right in the first newborn; (b) chest X-ray shows individual paracardial and basal shadings of the pulmonary parenchyma in the second newborn.
The placental tissue was sent for pathological and microbiological analyses. Pathological examination of placental tissue samples showed marginal hemorrhage and opaque membranes with yellow-green discoloration and purulent amniotic fluid. Microscopic analysis showed neutrophilic infiltrate of membranes and those overlying the chorionic plate with rare macrophages and without necrosis, including umbilical vasculitis. A diagnosis of acute chorioamnionitis was made (Figure 2). According to the Amsterdam consensus criteria for maternal and fetal inflammatory responses, our case was classified as Stage 2, Grade 2 [15]. Tests for the presence of genital mycoplasma (Ureaplasma urealyticum and Mycoplasma hominis) were negative, and real-time polymerase chain reaction (PCR) tests assessing the presence of Neisseria gonorrhoeae and Chlamydia trachomatis were negative. Applying the same examinations, the presence of the bacteria S. marcescens was discovered. Moreover, in a touch preparation of the placental tissue, dead cells were identified (up to 30 leukocytes in the visible range) [16]. After delivery on the third day of hospitalization, treatment was continued with amikacin (1 g/day) and ceftriaxone (2 g/day). On the ninth day of admission, the patient was discharged and treatment was continued according to the antibiogram, with ciprofloxacin at an oral dose of 1 g/day for the next 7 days. Control cervical and vaginal discharge samples were negative three days and two weeks after therapy.
Figure 2 Histological features of chorioamnionitis caused by Serratia marcescens. Photomicrographs of the placental tissue show neutrophilic infiltrate of membranes and those overlying the chorionic plate with rare macrophages and without necrotic debris; (a) hematoxylin and eosin staining, ×200; (b) hematoxylin and eosin staining, ×400; (c) hematoxylin and eosin staining, ×400.
Informed consent: Informed consent has been obtained from a mother for potentially descriptive information to be published in this article.
3 Discussion
According to the available data, an infection caused by S. marcescens results in a miscarriage or extremely preterm birth by an immunocompetent patient, thereby making this case very interesting [13]. Registered in 1960, this bacterial species is often described as a cause of nosocomial interhospital infections [2]. Although this species is sensitive to a wide range of available antibiotics, it is often difficult to exterminate this species from the facilities implicated in interhospital infections [2].
Van Ogtrop et al. followed an outbreak of colonization and infection with S. marcescens that occurred in a neonatal intensive care unit [17]. S. marcescens was isolated from five preterm infants between 25–30 weeks of gestation. Two infants developed fatal septicemia, and one infant experienced conjunctivitis due to S. marcescens [17]. Two infants were colonized, but did not display clinical signs of infection. All infants were treated with antibiotic regimens, including ciprofloxacin and gentamicin [17].
David et al. analyzed twenty-one patients who were infected or colonized in a neonatal unit over a 9-month period from 2001–2002 [18]. Twenty-two isolates were examined for antibiotic susceptibility, β-lactamase production, and genotype [18]. Random-amplified polymorphic deoxyribonucleic acid (DNA) PCR and pulsed-field gel electrophoresis revealed that two clones were present [18]. The first clone caused invasive clinical infection in four babies and was subsequently replaced by a noninvasive clone that affected 14 babies [18]. According to their production of prodigiosin, two different strains have been described: the first strain was nonpigmented, while the second exhibited pink-red pigmentation [18]. The clinical features suggested the difference in the scope of pathogenicities of these two strains. No environmental source was identified [18].
S. marcescens has only recently been implicated as a cause of miscarriages and preterm labor resulting from bacteremia and chorioamnionitis [9,10,12]. Prior rupture of membranes is not necessarily due to the development of an ascending amniotic infection [19]. It has been established that subclinical intrauterine infection may occur, even with intact membranes, leading to the absence of clinical signs of infection, despite clear histological signs of chorioamnionitis [20]. The way the infection occurred and spread in this case is not clear. In some cases, the growth and spread of the infection occurred from the vagina, which was confirmed by a vaginal swab [9,13,14]. S. marcescens is not part of the normal vaginal flora and is most commonly encountered as an opportunistic pathogen in nosocomial settings [21]. It is typically associated with the use of invasive devices or procedures (e.g., chorionic villus sampling, placement of a central venous line), repeated vaginal examinations after preterm prelabor rupture of membranes as well as with patients whose health is generally compromised [9,11,14]. It is also associated with poor hygiene in health care facilities (hands of personnel, contaminated irrigation solutions or disinfectants) and prior unsuccessful antibiotic treatments of patients [22]. In the hospital, Serratia species tend to colonize the respiratory and urinary tracts of adults rather than the gastrointestinal tract (2).
Amniocentesis is very important in the diagnosis of chorioamnionitis. This invasive procedure is followed by risks of miscarriage and transmission of the infection to the fetus [21]. On the other hand, a negative result cannot completely exclude chorioamnionitis, especially at an early stage [11]. In this case, this procedure was not performed. A review of the reported cases of Serratia marcescens chorioamnionitis is presented in Table 1.
Table 1 Review of the reported cases of Serratia marcescens chorioamnionitis
No Reference Year Age WG Immunocompetent host Source of infection Symptoms on admission Outcome Treatment Length of hospitalization
1. Kljakic et al. (Current study) 2020 26 25 Yes Unknown Scant vaginal bleeding, lower abdominal pain, fever Vaginal preterm delivery; Infants died two days after birth. Ceftriaxone (3 days). After delivery, the treatment was continued with Amikacin and Ceftriaxone (6 days) and followed by Ciprofloxacin according to the antibiogram (7 days) 9 days
2. Mak et al. [21] 2018 35 15–37 Yes Ascending infection from the vagina Fever, chills, rigor, runny nose, cough, sputum, headache, myalgia, vomiting undigested food Vaginal term delivery (uninfected newborn) Meropenem 24 weeks
3. Erenberg et al. [14] 2017 36 25–28 Yes Prolonged PPROM Chills, abdominal pain, sub-febrile fever, tachycardia, leukocytosis, fetal tachycardia Emergency cesarean delivery Amoxicillin/Clavulanic Acid (3 days), followed by Meropenem (6 days) 11 days
4. Vale-Fernandes et al. [13] 2015 31 15–16 Yes N/A Hyperthermia, hemicranial headache, nausea, vomiting, diarrhea Spontaneous abortion Ceftriaxone and Ampicillin (12 days), followed by only Ceftriaxone (2 days) 12 days
5. Chai et al. [12] 2011 32 12 No Unknown Amenorrhea, fever, chills, vomiting Fetal death followed by vacuum curettage Meropenem N/A
6. Meirowitz et al. [11] 2006 28 21–25 No Central catheter line Fever, chills, malaise, headache Emergency cesarean delivery Ceftriaxone (11 days), followed by Ertapenem (17 days), followed by Imipenem (14 days) 41 days
7. Shimizu et al. [10] 2003 26 10–20 Yes Urinary tract Gait disturbance, severe tenderness, flaring in the lower left extremity, fever Spontaneous abortion Cefotiam (5 days), followed by Ceftazidime (8 days), followed by Imipenem/Cilastatin (8 days). Second admission – Ceftriaxone and Imipenem/Cilastatin up to the abortion?, followed by Imipenem/Cilastatin (by the 7 day after the abortion 7) 40 days during first admission? Period of the second admission is N/A
8. Prosser et al. [9] 2003 38 19–21 Yes Chorionic-villus sampling Intermittent fevers, malaise. Spontaneous abortion Tobramycin and Cefepime (12 days) followed by Trimethoprim–sulfamethoxazole and Cefepime (2 weeks?) 12 days
Potentially, two mechanisms of fetal loss are associated with infection, and both are characteristic of advanced pregnancy. First, bacterial invasion of the amniotic cavity or fetoplacental membranes can stimulate labor of an immature fetus, and second, intrauterine infection of the fetus can probably occur as a result of the swallowing or inhaling of infected amniotic fluid and cause fetal pneumonitis and/or septicemia [20].
FGR is defined as a condition in which the fetus does not achieve its genetically determined growth potential [23]. FGR can be caused by a variety of factors, such as infections, the mother’s illnesses, and chromosomal disorders, but it primarily refers to anomalies in placental development that occur early in pregnancy [24,25]. The pathophysiology of discordant FGR remains insufficiently and inaccurately defined. Several recognized factors, categorized as maternal, fetal, and placental, influence the likelihood of discordant twins [26]. Altogether, with factors including intrauterine surroundings and utero-placental insufficiency, this condition can lead to discordant FGR [26].
Discordant fetal growth (with greater than 20% discordance) complicates 15% to 29% of twin pregnancies [27]. In a study involving 15,066 twin pregnancies, the rate of miscarriage was significantly increased when discordance was greater than 20%, especially in cases of monochorionic twin pregnancies [28]. It is important to note that the pregnancy in this case report was dichorionic. The increased pregnancy loss rate is attributed to monochorionicity of twin pregnancy [29].
In this case, infection by S. marcescens cannot be excluded as a cause of discordant growth. This is supported by the lack of awareness of the pregnancy period when the infection occurred. Previous studies have shown that chronic chorioamnionitis in some cases may be the cause of restrictive intrauterine growth of the fetus, especially in twin pregnancies [30]. Thus, it is reported, on rare occasions, that bacterial infections such as chlamydia, mycoplasma, listeria, and tuberculosis can cause restrictive intrauterine growth [31]. In addition, studies are required to examine the association between localization and/or different bacterial populations with the degree of oxygenation and maternal and fetal circulation. The immunomodulatory effect caused by bacterial infections of the placenta, hypothetically, may be the reason for the restrictive growth of the fetus and its subsequent rejection or preterm birth, and this needs to be confirmed by further research.
4 Conclusions
Although rare, S. marcescens can cause spontaneous miscarriages and, in this case, loss of extremely preterm birth of discordant twins in an immunocompetent patient. Infection by S. marcescens cannot be excluded as a cause of discordant growth and needs to be confirmed by further research.
Abbreviations
ACabdominal circumference
BPDbiparietal diameter
CRPC-reactive protein
DNAdeoxyribonucleic acid
EFWestimated fetal weight
FGRfetal growth restriction
FLfemur length
HChead circumference
Hgbhemoglobin
PCRpolymerase chain reaction
PLTplatelet count
RBCsred blood cells
WBCswhite blood cells
WGweeks of gestation
Acknowledgments
We would like to express special gratitude to our friend and colleague Duško Kljakić who died during the Covid 19 epidemic.
Conflict of interest: Authors state no conflict of interest.
Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | AMPICILLIN, CEFTRIAXONE | DrugsGivenReaction | CC BY | 33385065 | 19,704,876 | 2021 |
What was the dosage of drug 'AMPICILLIN'? | Serratia marcescens as a cause of unfavorable outcome in the twin pregnancy.
Several Serratia species are widely distributed in nature, but Serratia marcescens is the only species frequently isolated in hospitals. This pathogen is mainly responsible for nosocomial infection, mostly in immunocompromised hosts. A 26-year-old woman with a twin pregnancy, regularly controlled, was hospitalized at 24 + 5 weeks of gestation due to scant vaginal bleeding, lower abdominal pain, and body temperature up to 37.5°C. Gynecological examination revealed bleeding accompanied by dilatation of the cervix. The laboratory analyses revealed leukocytosis with elevated C-reactive protein (CRP). Treatment was initiated with intravenous antibiotic administration. After admission, fetal membranes spontaneously ruptured, and an extremely preterm dichorionic female twin birth occurred at 25 + 0 weeks of gestation. Both infants died two days after labor. Pathological and microbiological analyses revealed chorioamnionitis caused by S. marcescens. According to the antibiogram, antibiotic treatment was continued for the next 7 days. The examination of cervical and vaginal discharge samples was negative three days and two weeks after therapy. S. marcescens may cause spontaneous miscarriages and, in this important case, caused loss of discordant twins in an extremely preterm birth by an immunocompetent patient. Infection by S. marcescens cannot be excluded as a cause of discordant growth and needs to be confirmed by further research.
1 Introduction
Serratia marcescens is an aerobic (facultative anaerobic), motile, Gram-negative, enteric saprophytic rod of the Klebsiella–Enterobacter–Serratia division of the Enterobacteriaceae family [1]. S. marcescens is observed almost everywhere in nature, but it favors moist conditions [2]. In this paper, a case of S. marcescens placental infection is described as a cause of extremely preterm birth and loss of infants in twin pregnancy due to pneumonitis followed by respiratory insufficiency.
Infections during pregnancy are complex and important because the infection affects not only the mother, but also the fetus [3]. The duration and results of the infection depend on the number and virulence of the microbes, the immunobiological characteristics of the mother, the manner of spread of the infection, and the gestational period [4]. The immunobiological status of the mother is stressed given the depressed T lymphocyte function and frequent compositional alterations in biological flora in the birth canal during pregnancy, which significantly contributes to the development of infections [5].
As a result of infections during pregnancy, fetal membranes may become infected (chorioamnionitis and intraamniotic infection syndrome), resulting in premature placental abruption and spontaneous miscarriage or preterm birth [6]. Due to the very high infant death rate under these conditions, the peripartum morbidity of the mother is also high [7]. In line with these findings, Serratia bacteremia has a high mortality rate of approximately 37% within six months [8]. During pregnancy, this infection is a rare but potentially fatal disorder that is also associated with chorioamnionitis or placental abscess, miscarriages, and preterm deliveries [9,10,11,12,13,14].
2 Case report
A 26-year-old (gravida 2, para 1), Rh-negative, childbearing mother with an Rh-positive partner undergoing a regularly controlled second dichorionic twin pregnancy was the subject of this study. The first pregnancy proceeded normally and yielded a positive outcome. Due to uterine cervical insufficiency during this pregnancy, a cerclage was placed at 15 weeks of gestation (WG). Discordant fetal growth restriction (FGR) was diagnosed by ultrasound at 24 + 3 WG based on an estimated discordance of approximately 25% (ultrasound parameters of the first twin: 61 mm biparietal diameter (BPD), 45 mm femur length (FL), 19.8 cm abdominal circumference (AC), 22.6 cm head circumference (HC), and approximately 530 g estimated fetal weight (EFW); ultrasound parameters of the 2nd twin: 65 mm BPD, 48 mm FL, 21 cm AC, 23.8 cm HC, and approximately 730 g EFW.
The patient was admitted to the hospital at 24 + 5 WG for scant vaginal bleeding, lower abdominal pain, and body temperature up to 37.5°C. Gynecological examination revealed bleeding within dilatation of the cervix with a diameter of 1 cm near the cerclage. The laboratory analyses revealed leukocytosis with elevated C-reactive protein (CRP) (28.3 × 109/L white blood cells (WBCs), 3.50 × 109/L red blood cells (RBCs), 108 g/L hemoglobin (Hgb), 385 × 109/L platelet count (PLT), and 28.5 mg/L CRP. Other laboratory analyses were in range with reference values. Treatment was initiated with intravenous administration of ceftriaxone at a dose of 2 g/day. Immediately after admission, fetal membranes spontaneously ruptured, and the mother experienced uterine contractions. The cerclage was removed, and an extremely preterm dichorionic female twin birth with discordant FGR occurred at 25 + 0 WG. The first twin weighed 560 g and had an AS of 2/2, and the second twin weighed 780 g and had an AS of 2/2. Both female infants had an altered state of consciousness and were edematous, hypotonic, apneic, and bradycardic, with multiple hematomas at the extremities and in the occipital region, and had leukocytosis (95.6 × 109/L WBCs in the first and 38.9 × 109/L WBCs in the second newborn). Swabs of the umbilical cord, nose, and anus were negative for both infants. Chest X-ray of the first newborn showed decreased transparency of the pulmonary parenchyma to the left with a clearly limited presence in the upper lobe area to the right (Figure 1a). Radiography of the second infant confirmed individual paracardial and basal shadings of the pulmonary parenchyma (Figure 1b). Ultrasound indicated the immaturity of the brain parenchyma in both newborns with asymmetry of the ventricular system and plexus. Both infants were attached to mechanical ventilation, followed by treatment with electrolytes, a prophylactic dose of corticosteroids, and antibiotic therapy. The infants died two days after birth due to respiratory failure despite resuscitation.
Figure 1 Chest X-ray of the newborns. (a) Image shows decreased transparency of the pulmonary parenchyma to the left with a clearly limited presence in the upper lobe area to the right in the first newborn; (b) chest X-ray shows individual paracardial and basal shadings of the pulmonary parenchyma in the second newborn.
The placental tissue was sent for pathological and microbiological analyses. Pathological examination of placental tissue samples showed marginal hemorrhage and opaque membranes with yellow-green discoloration and purulent amniotic fluid. Microscopic analysis showed neutrophilic infiltrate of membranes and those overlying the chorionic plate with rare macrophages and without necrosis, including umbilical vasculitis. A diagnosis of acute chorioamnionitis was made (Figure 2). According to the Amsterdam consensus criteria for maternal and fetal inflammatory responses, our case was classified as Stage 2, Grade 2 [15]. Tests for the presence of genital mycoplasma (Ureaplasma urealyticum and Mycoplasma hominis) were negative, and real-time polymerase chain reaction (PCR) tests assessing the presence of Neisseria gonorrhoeae and Chlamydia trachomatis were negative. Applying the same examinations, the presence of the bacteria S. marcescens was discovered. Moreover, in a touch preparation of the placental tissue, dead cells were identified (up to 30 leukocytes in the visible range) [16]. After delivery on the third day of hospitalization, treatment was continued with amikacin (1 g/day) and ceftriaxone (2 g/day). On the ninth day of admission, the patient was discharged and treatment was continued according to the antibiogram, with ciprofloxacin at an oral dose of 1 g/day for the next 7 days. Control cervical and vaginal discharge samples were negative three days and two weeks after therapy.
Figure 2 Histological features of chorioamnionitis caused by Serratia marcescens. Photomicrographs of the placental tissue show neutrophilic infiltrate of membranes and those overlying the chorionic plate with rare macrophages and without necrotic debris; (a) hematoxylin and eosin staining, ×200; (b) hematoxylin and eosin staining, ×400; (c) hematoxylin and eosin staining, ×400.
Informed consent: Informed consent has been obtained from a mother for potentially descriptive information to be published in this article.
3 Discussion
According to the available data, an infection caused by S. marcescens results in a miscarriage or extremely preterm birth by an immunocompetent patient, thereby making this case very interesting [13]. Registered in 1960, this bacterial species is often described as a cause of nosocomial interhospital infections [2]. Although this species is sensitive to a wide range of available antibiotics, it is often difficult to exterminate this species from the facilities implicated in interhospital infections [2].
Van Ogtrop et al. followed an outbreak of colonization and infection with S. marcescens that occurred in a neonatal intensive care unit [17]. S. marcescens was isolated from five preterm infants between 25–30 weeks of gestation. Two infants developed fatal septicemia, and one infant experienced conjunctivitis due to S. marcescens [17]. Two infants were colonized, but did not display clinical signs of infection. All infants were treated with antibiotic regimens, including ciprofloxacin and gentamicin [17].
David et al. analyzed twenty-one patients who were infected or colonized in a neonatal unit over a 9-month period from 2001–2002 [18]. Twenty-two isolates were examined for antibiotic susceptibility, β-lactamase production, and genotype [18]. Random-amplified polymorphic deoxyribonucleic acid (DNA) PCR and pulsed-field gel electrophoresis revealed that two clones were present [18]. The first clone caused invasive clinical infection in four babies and was subsequently replaced by a noninvasive clone that affected 14 babies [18]. According to their production of prodigiosin, two different strains have been described: the first strain was nonpigmented, while the second exhibited pink-red pigmentation [18]. The clinical features suggested the difference in the scope of pathogenicities of these two strains. No environmental source was identified [18].
S. marcescens has only recently been implicated as a cause of miscarriages and preterm labor resulting from bacteremia and chorioamnionitis [9,10,12]. Prior rupture of membranes is not necessarily due to the development of an ascending amniotic infection [19]. It has been established that subclinical intrauterine infection may occur, even with intact membranes, leading to the absence of clinical signs of infection, despite clear histological signs of chorioamnionitis [20]. The way the infection occurred and spread in this case is not clear. In some cases, the growth and spread of the infection occurred from the vagina, which was confirmed by a vaginal swab [9,13,14]. S. marcescens is not part of the normal vaginal flora and is most commonly encountered as an opportunistic pathogen in nosocomial settings [21]. It is typically associated with the use of invasive devices or procedures (e.g., chorionic villus sampling, placement of a central venous line), repeated vaginal examinations after preterm prelabor rupture of membranes as well as with patients whose health is generally compromised [9,11,14]. It is also associated with poor hygiene in health care facilities (hands of personnel, contaminated irrigation solutions or disinfectants) and prior unsuccessful antibiotic treatments of patients [22]. In the hospital, Serratia species tend to colonize the respiratory and urinary tracts of adults rather than the gastrointestinal tract (2).
Amniocentesis is very important in the diagnosis of chorioamnionitis. This invasive procedure is followed by risks of miscarriage and transmission of the infection to the fetus [21]. On the other hand, a negative result cannot completely exclude chorioamnionitis, especially at an early stage [11]. In this case, this procedure was not performed. A review of the reported cases of Serratia marcescens chorioamnionitis is presented in Table 1.
Table 1 Review of the reported cases of Serratia marcescens chorioamnionitis
No Reference Year Age WG Immunocompetent host Source of infection Symptoms on admission Outcome Treatment Length of hospitalization
1. Kljakic et al. (Current study) 2020 26 25 Yes Unknown Scant vaginal bleeding, lower abdominal pain, fever Vaginal preterm delivery; Infants died two days after birth. Ceftriaxone (3 days). After delivery, the treatment was continued with Amikacin and Ceftriaxone (6 days) and followed by Ciprofloxacin according to the antibiogram (7 days) 9 days
2. Mak et al. [21] 2018 35 15–37 Yes Ascending infection from the vagina Fever, chills, rigor, runny nose, cough, sputum, headache, myalgia, vomiting undigested food Vaginal term delivery (uninfected newborn) Meropenem 24 weeks
3. Erenberg et al. [14] 2017 36 25–28 Yes Prolonged PPROM Chills, abdominal pain, sub-febrile fever, tachycardia, leukocytosis, fetal tachycardia Emergency cesarean delivery Amoxicillin/Clavulanic Acid (3 days), followed by Meropenem (6 days) 11 days
4. Vale-Fernandes et al. [13] 2015 31 15–16 Yes N/A Hyperthermia, hemicranial headache, nausea, vomiting, diarrhea Spontaneous abortion Ceftriaxone and Ampicillin (12 days), followed by only Ceftriaxone (2 days) 12 days
5. Chai et al. [12] 2011 32 12 No Unknown Amenorrhea, fever, chills, vomiting Fetal death followed by vacuum curettage Meropenem N/A
6. Meirowitz et al. [11] 2006 28 21–25 No Central catheter line Fever, chills, malaise, headache Emergency cesarean delivery Ceftriaxone (11 days), followed by Ertapenem (17 days), followed by Imipenem (14 days) 41 days
7. Shimizu et al. [10] 2003 26 10–20 Yes Urinary tract Gait disturbance, severe tenderness, flaring in the lower left extremity, fever Spontaneous abortion Cefotiam (5 days), followed by Ceftazidime (8 days), followed by Imipenem/Cilastatin (8 days). Second admission – Ceftriaxone and Imipenem/Cilastatin up to the abortion?, followed by Imipenem/Cilastatin (by the 7 day after the abortion 7) 40 days during first admission? Period of the second admission is N/A
8. Prosser et al. [9] 2003 38 19–21 Yes Chorionic-villus sampling Intermittent fevers, malaise. Spontaneous abortion Tobramycin and Cefepime (12 days) followed by Trimethoprim–sulfamethoxazole and Cefepime (2 weeks?) 12 days
Potentially, two mechanisms of fetal loss are associated with infection, and both are characteristic of advanced pregnancy. First, bacterial invasion of the amniotic cavity or fetoplacental membranes can stimulate labor of an immature fetus, and second, intrauterine infection of the fetus can probably occur as a result of the swallowing or inhaling of infected amniotic fluid and cause fetal pneumonitis and/or septicemia [20].
FGR is defined as a condition in which the fetus does not achieve its genetically determined growth potential [23]. FGR can be caused by a variety of factors, such as infections, the mother’s illnesses, and chromosomal disorders, but it primarily refers to anomalies in placental development that occur early in pregnancy [24,25]. The pathophysiology of discordant FGR remains insufficiently and inaccurately defined. Several recognized factors, categorized as maternal, fetal, and placental, influence the likelihood of discordant twins [26]. Altogether, with factors including intrauterine surroundings and utero-placental insufficiency, this condition can lead to discordant FGR [26].
Discordant fetal growth (with greater than 20% discordance) complicates 15% to 29% of twin pregnancies [27]. In a study involving 15,066 twin pregnancies, the rate of miscarriage was significantly increased when discordance was greater than 20%, especially in cases of monochorionic twin pregnancies [28]. It is important to note that the pregnancy in this case report was dichorionic. The increased pregnancy loss rate is attributed to monochorionicity of twin pregnancy [29].
In this case, infection by S. marcescens cannot be excluded as a cause of discordant growth. This is supported by the lack of awareness of the pregnancy period when the infection occurred. Previous studies have shown that chronic chorioamnionitis in some cases may be the cause of restrictive intrauterine growth of the fetus, especially in twin pregnancies [30]. Thus, it is reported, on rare occasions, that bacterial infections such as chlamydia, mycoplasma, listeria, and tuberculosis can cause restrictive intrauterine growth [31]. In addition, studies are required to examine the association between localization and/or different bacterial populations with the degree of oxygenation and maternal and fetal circulation. The immunomodulatory effect caused by bacterial infections of the placenta, hypothetically, may be the reason for the restrictive growth of the fetus and its subsequent rejection or preterm birth, and this needs to be confirmed by further research.
4 Conclusions
Although rare, S. marcescens can cause spontaneous miscarriages and, in this case, loss of extremely preterm birth of discordant twins in an immunocompetent patient. Infection by S. marcescens cannot be excluded as a cause of discordant growth and needs to be confirmed by further research.
Abbreviations
ACabdominal circumference
BPDbiparietal diameter
CRPC-reactive protein
DNAdeoxyribonucleic acid
EFWestimated fetal weight
FGRfetal growth restriction
FLfemur length
HChead circumference
Hgbhemoglobin
PCRpolymerase chain reaction
PLTplatelet count
RBCsred blood cells
WBCswhite blood cells
WGweeks of gestation
Acknowledgments
We would like to express special gratitude to our friend and colleague Duško Kljakić who died during the Covid 19 epidemic.
Conflict of interest: Authors state no conflict of interest.
Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | UNK UNK, BID | DrugDosageText | CC BY | 33385065 | 19,704,876 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypotension'. | Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis.
A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.
The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.
In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.
The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).
Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.
Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1,2 Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3,4
Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5, 6, 7 In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7, 8, 9 Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8 as well as following administration of antimycobacterial therapy to patients with this disease.10 The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10,11 Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11 A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12 We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease.
Patients and Methods
Trial Design and Objectives
This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses.
Protocol Development and Oversight
The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13 This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen.
Interventions
Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269).
Population Eligibility and Randomization
Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1 Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least 5% on serial measurements over 24 months; (2) radiographic progression in chest imaging on side-by-side comparison; or (3) decline in dyspnea score, as measured by using the Transition Dyspnea Index. Prior to randomization, participants were assessed for peripheral immune responses to ESAT-6 or evidence of peripheral anergy as defined by absence of responses to phytohemagglutinin. If either of those conditions were present, the subject was enrolled. Finally, participants were required to have evidence of parenchymal or nodal disease on chest radiograph. Site-specific pulmonologists who were unaffiliated with the CLEAR trial read all site-specific lung function tests.
Sample size was calculated for the primary end point: change from baseline of FVC percent predicted. Using data from participants with chronic pulmonary sarcoidosis treated with infliximab,14 we obtained the SD of 7.7 for the primary end point. A sample size of 51 completed participants per arm was needed to have 90% power to detect a 5% difference in change of FVC percent predicted from baseline.
The major exclusion criteria were as follows:(1) Inability to obtain consent.
(2) Age < 18 years.
(3) Female participants of childbearing potential not willing to use one of the following methods of birth control for the duration of the study and 90 days following study completion: condoms, sponge, foams, jellies, diaphragm, nonhormonal intrauterine device, a vasectomized sole partner, or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test result at screening visit was required if the female subject was of childbearing potential.
(4) FVC predicted value < 45%.
(5) End-stage fibrotic pulmonary disease.
(6) Significant underlying liver disease.
(7) Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
(8) Allergy or intolerance to albuterol.
(9) Poor venous access for obtaining blood samples.
(10) History of active TB, close contact with a person with active TB within the 6 months prior to the screening visit, or a positive purified protein derivative skin test result.
(11) Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation (eg, respiratory, cardiac, neurologic, musculoskeletal, or seizure disorders).
(12) Use of an investigational drug within 30 days prior to screening or within five half-lives of the agent, whichever is longer.
(13) Currently receiving > 40 mg of prednisone.
(14) Alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal.
(15) Leukopenia, as defined by a WBC count < 3.0 cells/mm3 or absolute neutrophil count < 1,000/μL.
(16) Breastfeeding.
(17) Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis.
(18) If the patient is on immunomodulators, they must be on a regimen for 3 months or longer and on a stable dose for > 4 weeks.
(19) Family or personal history of long QT interval.
(20) Most recent nuclear medicine scan or echocardiogram (if performed) showing cardiac ejection fraction < 35%.
(21) Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotic, antiretroviral, or antifungal agents within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis.
(22) Any significant finding in the patient’s medical history or physical or psychiatric examination prior to or following randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol.
(23) Taking medications that, in the opinion of the investigator, would affect patient safety when taken with the antibiotics of the CLEAR regimen.
(24) History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit.
Patients were assigned to receive the CLEAR or placebo regimen by using a block randomization stratified according to site and use of prednisone ≥ 10 mg or not. Randomization lists were generated and distributed to site pharmacies by a statistician at Vanderbilt University Medical Center not associated with the study.
Measurement of Treatment Completion
Patients were requested to bring all remaining doses of every trial drug to each visit for pill counts. Treatment completion for the per-protocol analysis was defined as administration of at least 90% of the doses within 16 weeks.
Measurement of Safety During Treatment
At each follow-up visit, participants were questioned and examined for adverse events. Suspected adverse events were investigated, managed, and reported according to a standardized protocol. Information about suspected adverse events was reviewed and graded by the site-specific principal investigator and clinical coordinator. The severity of adverse events was judged according to the Common Toxicity Criteria for Adverse Events version 4.0. The events were categorized as follows: an adverse event that was not related to a trial drug; an adverse event of grade 1 or 2 that was related to a trial drug (not serious); an adverse event of grade 3 or 4 that was related to a trial drug (generally considered to lead to trial drug discontinuation if related to a trial drug); or a grade 5 event (death) that was related to a trial drug. Each adverse event resulting in organ impairment, hospitalization, or death was defined as a serious adverse event (SAE). An SAE was reported and reviewed by the institutional review board, as well as the four-member Data Safety Monitoring Board. The board provided oversight regarding safety for continuation of the study.
Oversight
This trial was approved by the Vanderbilt University Human Research Protection Program and by the institutional review board at each participating site. All the authors vouch for the accuracy and completeness of the data and analyses presented and for the compliance of the trial to the protocol.
Statistical Analysis
This randomized Phase II clinical trial was conducted to determine if CLEAR elicits a statistically significant (two-sided value P < .05) improvement in respiratory performance, the 6MWD, SGRQ, and immune responses against ESAT-6. Ninety-seven patients were randomized to treatment from May 5, 2014, to December 13, 2018, of whom 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were cleaned and locked for final analysis on April 18, 2019. The primary end point was baseline to 16-week change in preinhaler FVC as percent predicted. We defined the 16-week postrandomization FVC percent predicted value measurement as the value closest to 16 weeks from randomization within a window of 12 to 20 weeks from randomization.
The primary comparison between the CLEAR and placebo arms was conducted on an intention-to-treat (as randomized) basis among patients with both baseline and 16-week outcomes (N = 97). Unless otherwise stated, mean, SE, and comparative P values were estimates with multiple imputation using predictive mean matching with aregImpute, as previously described.15,16 The multiple imputation data sets were summarized according to Rubin’s rules.17 Unless otherwise noted, figures represent the mean change score ± the SE computed by using Rubin’s rules for imputed data. Change scores for secondary end points were compared by using the linear model formulation of the two-sample test between groups over 100 imputed data sets. The paired Student t test for multiply imputed data was used to compare baseline and 16-week change scores within each treatment group at 8 and 16 weeks. All analyses were repeated for a per-protocol population of patients (n = 72). Analysis of ESAT-6 and adverse events was not based on imputed data. The ESAT-6 analysis was the only within-group comparison and was conducted by using a Student paired t test, comparing baseline with 16-week values within their randomization cohort. The number of subjects experiencing an SAE and separately an adverse event (adverse events not including SAEs) was compared between treatment arms by using the paired or unpaired Student t test.
Results
Trial Participants
We screened 446 potential patients from May 2014 through December 2018, of whom 97 were enrolled and randomized to treatment (Fig 1). The most common reasons for exclusion from study participation were as follows: (1) significant comorbid conditions; (2) a history of a drug interaction between one of the CLEAR antibiotics with a medication that the patient was currently receiving; (3) patient declined to participate; (4) pulmonary hypertension treatment; (5) concerns for noncompliance with study visits; and (6) Scadding stage IV fibrosis detected on a chest radiograph.Figure 1 Consort Diagram of Phase IIB investigation of the efficacy of antimycobacterial therapy against progressive pulmonary sarcoidosis. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; LTBI = latent TB infection.
The demographic and clinical characteristics of all study participants according to their randomization group are shown in Table 1. Of the 97 enrolled subjects, baseline characteristics were well balanced across treatment arms. Approximately one-half of the population (n = 50 [52%]) was female, and the majority were White (n = 68 [70%]), with approximately one-third African American (n = 28 [29%]). A possible balance exception was sex (59% women in the placebo group and 44% women in the CLEAR group). Although not a planned analysis, analysis of covariance of sex (P = .996) with treatment group (P = .903) on nonimputed data, as with their interaction (P = .678), suggests no confounding by sex.Table 1 Patient Demographic Characteristics According to Therapeutic Regimen
Characteristic CLEAR Placebo Combined
(n = 49) (n = 48) (N = 97)
Age, mean ± SD, y 54.5 ± 9.8 54.5 ± 9.8 54.5 ± 10
Sex
Male 20 (41%) 27 (56%) 47 (48%)
Female 29 (59%) 21 (44%) 50 (52%)
Race
African American 15 (31%) 13 (27%) 28 (29%)
White 34 (69%) 34 (71%) 68 (70%)
Hawaiian or Pacific Islander 0 (0) 1 (2%) 1 (1%)
Ethnicity
Non-Hispanic/nor Latino 48 (98%) 46 (96%) 94 (97%)
Hispanic/Latino 1 (2%) 2 (4%) 3 (3%)
Baseline end points
Preinhaler FVC % 77.3 ± 13.7 75.5 ± 14.5 75.4 ± 14.1
6-min walk test, ma 416.2 ± 140.7 416.4 ± 105.2 416.3 ± 123.5
SGRQ activityb 57.7 ± 23.2 55.5 ± 24.5 56.6 ± 23.8
SGRQ impactb 34.8 ± 22.2 32.9 ± 19.8 33.8 ± 20.9
SGRQ symptomsb 53.9 ± 23.8 50.5 ± 19.3 52.2 ± 21.7
SGRQ totalb 44.9 ± 21.1 42.7 ± 18.7 43.8 ± 19.9
Immunosuppression
Patients on prednisone (mean dosage) 23 (47%) (10 mg) 19 (40%) (10 mg) 42 (43%) (10 mg)
Patients on a DMA 19 (39%) 17 (35%) 36 (37%)
Patients on a biologic agent 1 (2%) 1 (2%) 2 (4%)
Patients on prednisone plus a DMA or biologic agent 10 (20%) 6 (13%) 16 (16%)
Patients on any combination of prednisone, DMA, or biologic agent 11 (22%) 8 (17%) 19 (20%)
ESAT-6 positivity
Yes 39 (80%) 36 (75%) 75 (77%)
Equivocal 10 (20%) 12 (25%) 25 (23%)
CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; DMA = disease-modifying agent; ESAT-6 = early secreted antigenic target of 6 kDa.
a N = 48 for CLEAR and placebo groups.
b N = 48 and N = 47, for CLEAR and placebo groups, respectively.
The clinical data were analyzed via intention-to-treat and per protocol. No subjects were excluded from the intention-to-treat analysis. In the per-protocol analysis, 25 (12 in the active arm and 13 in the placebo arm) of the 97 patients were excluded because of failure to take > 4 weeks of the prescribed regimen (CLEAR, n = 8; placebo, n = 4), alteration in clinical immunosuppressive regimen while on study drugs (CLEAR, n = 1; placebo, n = 3), initiation of non-study antibiotics during study participation (CLEAR, n = 1; placebo, n = 3), and found to be receiving antibiotics with antimycobacterial therapy, such as trimethoprim-sulfamethoxazole, at the time of enrollment (CLEAR, n = 2; placebo, n = 3). The remaining 72 subjects were included in the per-protocol analysis.
Efficacy
In the intention-to-treat analysis, there were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between the CLEAR and placebo groups (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64) (Fig 2A, Table 2). Eight-eight patients experienced follow-up during the 12- to 20-week postrandomization window. Median (interquartile range) and mean ± SD of time to the date of FVC percent measurement was 17 (16.1-18) weeks and 17.5 ± 1.9 weeks, respectively. Time to primary end point measurement was equivalent between treatment groups, with a median (interquartile range) of 17 (16.2-18) weeks for placebo and 17.2 (16.2-18.0) weeks for CLEAR II patients. Mean ± SD values were 17.5 ± 1.9 and 17.4 ± 1.8. Evaluation of other physiological parameters, such as 6MWD (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = .91) revealed no statistically significant differences (Fig 2B). A negative change in the SGRQ score reflects an improvement in quality of life. The SRGQ did reveal statistically and clinically significant differences in favor of the placebo group (placebo, –7.97; CLEAR II, –1.52; P = .028, minimal clinically important difference = 4.0).Figure 2 A-B, Graphic depiction of intention-to-treat assessment of physiological parameters such as FVC and 6-min walk distance in 97 subjects with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, There were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between 49 CLEAR and 48 placebo subjects (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64). B, Evaluation of 6-min walk distance (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = 0.91) revealed no statistically significant difference. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Table 2 Physiological and Qualitative End Point Analyses
Variable Placebo CLEAR P Value
Intent-to-treat population
Preinhaler FVC % 0.02 ± 1.47 –1.06 ± 1.85 .640
6-min walk distance 12.40 ± 12.35 9.78 ± 19.31 .908
SGRQ activity –7.15 ± 3.28 –0.96 ± 2.87 .162
SGRQ impact –7.45 ± 2.64 –0.61 ± 2.78 .057
SGRQ symptoms –10.15 ± 3.45 –5.62 ± 3.22 .331
SGRQ total –7.97 ± 2.01 –1.52 ± 2.17 .028
Per-protocol group
Preinhaler FVC % 0.42 ± 1.48 –0.74 ± 1.75 .616
6-min walk distance 6.27 ± 11.99 36.35 ± 22.32 .242
SGRQ activity –4.25 ± 2.39 –1.45 ± 2.91 .458
SGRQ impact –7.97 ± 2.51 –1,10 ± 2.62 .061
SGRQ symptoms –9.78 ± 3.60 –8.07 ± 3.39 .730
SGRQ total –6.97 ± 2.13 –2.32 ± 2.32 .141
Imputed mean ± SE of baseline to 16-week differences in measurements. P values are from imputation-based two-sample Student t test. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; SGRQ = St. George’s Respiratory Questionnaire.
In the per-protocol analysis, 72 subjects were analyzed following removal of 25 patients prior to data analysis due to factors outlined in the protocol. Comparison of baseline vs week 16 end points of the remaining 72 patients revealed that there were no statistically differences in the primary end point (the change from baseline in percent predicted FVC) between 37 CLEAR-treated patients compared with 35 patients receiving placebo (CLEAR –0.74% vs placebo 0.42%; P = .62) (Fig 3A, Table 2). Evaluation of other physiological and qualitative end points revealed no significant differences; for example, there were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = .242) (Fig 3B). The SGRQ also revealed no significant differences in the total score between the groups (placebo, –6.9; CLEAR, –2.3; imputed two-sample Student t test, P = .14). CLEAR-treated patients had less improvement in activity, impact, and symptoms compared with patients receiving placebo.Figure 3 A-B, Graphic depiction of per-protocol assessment of physiologic parameters, such as FVC and placebo in 97 patients with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, Comparison of baseline vs week 16 end points of 72 subjects revealed that there were no statistically differences in the primary end point (change from baseline in percent predicted FVC) between 37 CLEAR subjects compared with 35 placebo subjects (CLEAR –0.74% vs placebo 0.42%; imputed two-sample Student t test, P = .62). B, Evaluation of 6-min walk distance revealed no significant difference among patients randomized to the CLEAR or the placebo regimen (36.4 m vs 6.3 m; imputed two-sample Student t test, P = .242). CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Although there was no significant baseline difference in ESAT-6-specific spot-forming units between the two groups (unpaired Student t test, P = .48) (Fig 4A), there was a significant difference in the spot-forming units following 16 weeks of therapy. There was no significant change in 38 subjects randomized to receive placebo (paired Student t test, P = .26) (Fig 4B); however, a significant decline in the ESAT-6 spot-forming units among the 31 patients randomized to the CLEAR regimen (paired Student t test, P = .0003) (Fig 4C). Only subjects for whom baseline and 16-week values were available were included in this analysis.Figure 4 Comparison of ESAT-6 immune responses at baseline (n = 69 subjects) (A), as well as baseline to 16 weeks among patients with sarcoidosis randomized to either the placebo (n = 38 subjects) (B) or CLEAR (n = 31 subjects) (C) regimen. ESAT-6 = early secreted antigenic target of 6 kDa; NS = not significant; PBMC = peripheral blood mononuclear cells; SFU = spot-forming units.
Safety
At each follow-up visit, participants were evaluated for adverse events. A total of 75 adverse events were noted in 39 subjects (e-Table 1). Any adverse event resulting in organ impairment, hospitalization, or death was defined as an SAE. The number of SAEs was similar for CLEAR (n = 4) and placebo (n = 3) (P = .72) (Table 3). Three of the four SAEs in the CLEAR cohort were believed to be related to study drugs; none was believed to be related in the placebo cohort. There were no deaths in this trial.Table 3 SAEs Throughout the Study
SAE Number Event Group Institution Date Anticipated Caused by Therapy
1 Leukopenia Active Cincinnati 08/14/2016 Yes Probable
2 Pneumonia Active Cincinnati 11/06/2014 Yes Probable
3 Neurosarcoidosis Active Vanderbilt 12/28/2016 No Not related
4 Hypotension Active AMC 01/29/2018 Yes Probable
5 Sepsis from abscess Placebo Cleveland 07/18/2017 No Not related
6 Postoperative infection Placebo Cleveland 11/14/2014 No Unlikely
7 Pneumonia Placebo Cleveland 06/04/2018 No Not related
AMC = Albany Medical College; SAE = severe adverse event.
Discussion
In this randomized, double-blind, placebo-controlled trial of CLEAR therapy, we observed no benefit from the study intervention on pulmonary function, for both the intention-to-treat and per-protocol analyses. Most secondary end points, such as 6MWD and SGRQ, showed no significant improvement from CLEAR, and SGRQ was worse at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated subjects, but no change was observed among those randomized to receive placebo (Figs 3, 4).
Although viable mycobacteria have been proposed to be causative agents for sarcoidosis, the current study provides no evidence to support that hypothesis. The current results are discordant from a randomized trial in which CLEAR therapy was beneficial for cutaneous sarcoidosis, and they also diverge from an uncontrolled report of CLEAR therapy.10,11 One explanation for the failure of CLEAR therapy is that the underlying hypothesis regarding the cause of sarcoidosis is incorrect. This explanation accords with the failure of prior studies to culture mycobacteria from sarcoidosis tissues.18,19
Other explanations for the failure of CLEAR therapy should also be considered. The inclusion criteria were designed to enroll a population with actively progressing sarcoidosis, but the precision of the longitudinal data supporting progression, and the long time window for demonstrating progression, are both problematic and may have biased the study population to include patients with relatively stable, adequately controlled disease.20 Progression in the placebo group on stable therapy would not be expected in a 16-week time frame. Active withdrawal of anti-sarcoidosis medications may be necessary to uncover relative treatment benefits if the effect size is modest, but this study required stable dosing throughout the treatment period. It is also possible that the treatment duration was too short to discern efficacy of therapy; medications such as methotrexate require up to 6 months to effect benefit in pulmonary sarcoidosis.21 Antibiotic therapy may not result in improved FVC; one study noted that these patients may continue to experience an FVC decline, but it occurs at a significantly lower rate than patients who were not successfully treated.22 Finally, FVC may be an insensitive marker of treatment effect; it has previously been shown to correlate poorly with symptoms and with chest imaging.23,24 However, the absence of any observable clinical benefits argues that the end point chosen here is likely not the cause of the negative result.
Immune responses against mycobacterial antigens, such as ESAT-6 and katG, are present in patients with active sarcoidosis disease.8,25,26 Independent investigators found that, using the ELISpot assay, antimycobacterial responses disappear with clinical resolution of sarcoidosis.8 Immune responses against ESAT-6 have also been detected with active or latent TB, as well as other nontuberculous mycobacteria infections27, 28, 29; these responses decline with effective antimycobacterial therapy.30, 31, 32 A significant decline in the ESAT-6 immune responses among subjects randomized to receive CLEAR (but not placebo) is provocative and of uncertain significance. It is unlikely that the decrease in ESAT-6 response in the CLEAR group is due to an immunosuppressant effect of one or more antibiotics in the treatment regimen because we previously reported improved immune function, including enhanced T-cell proliferative capacity and increased IL-2 and interferon-γ secretion, as well as augmented JAK-STAT signaling from sarcoidosis CD4+ T cells, following completion of the CLEAR regimen.11 The improvement in cellular immunity with CLEAR treatment of sarcoidosis could result in the augmented capacity to remove pathogenic microbial antigens such as ESAT-6. In addition, because the removal of microbial antigens such as ESAT-6 during treatment of mycobacterial infection reduces expression of profibrotic cytokines such as IL-17A, this mechanism may also mitigate the development of lung fibrosis during the treatment of sarcoidosis. The discrepancy between measurable declines in a virulence factor associated with active mycobacterial replication (ESAT-6) and the negative results of the current study remain unexplained.
It may be that mycobacterial antigens are important initial triggers of some cases of sarcoidosis, as suggested by persistence of mycobacterial antigens in sarcoidosis tissues,7 but viable infection is not integral to the perpetuation or progression of the disease. Also, because the study design did not obtain any samples to exclude the presence of infection in the subjects, it remains possible that the effects of CLEAR resulted in changes in the microbiome, which could then affect immune responses by changing the presence of microbial antigens. Future investigation regarding the impact of the CLEAR regimen on preventing further lung deterioration is warranted.
The current study did have some limitations. The number of subjects was relatively small. Twenty-five of the 97 patients were excluded from the per-protocol analysis, representing approximately 26% of the enrolled subjects. Twelve of those subjects (CLEAR, n = 8; placebo, n = 4) were excluded due to taking < 4 weeks of study medications, making it more difficult to assess the impact of 16 weeks of CLEAR therapy on the primary and secondary end points. Due to the pill burden and toxicities associated with a four-drug regimen, difficulty adhering to antimycobacterial therapy is well documented.33, 34, 35 Toxicities, such as myalgias and arthralgias from azithromycin and levofloxacin, as well as fatigue from rifabutin, may have affected the SGRQ score, masking our ability to clearly delineate an anti-sarcoidosis effect. Higher SGRQ scores were noted among CLEAR-treated patients experiencing these toxicities. Another limitation is the failure to include patients with disease for < 1 year. We did not include patients within 1 year of diagnosis because it was believed that differentiation of drug efficacy from spontaneous resolution would be too difficult. However, improvement in lung function among patients with TB is more likely if patients are < 40 years of age and do not have chronic sequelae.36 Future sarcoidosis clinical investigations should include patients within 1 year of their diagnosis, longer follow-up period assessment for potential steroid-sparing effect, and CT or PET scans. Several studies have shown that increased activity according to a PET scan is a useful predictor of treatment-responsive pulmonary sarcoidosis.37,38 PET scanning was not included in the current study because the information at time of study implementation was incomplete, and the cost of this as an exploratory analysis was prohibitive.
Conclusions
In a cohort of patients with progressive pulmonary sarcoidosis, the CLEAR therapy did not result in significant improvement in percent predicted FVC but, instead, was associated with significant declines in ESAT-6-specific immune responses.
Supplementary Data
e-Online Data
Acknowledgments
Author contributions: W. P. D. had full access to all the data following study completion and assumes full responsibility for the integrity of the data and the accuracy of the data analysis. W. P. D., D. A. C., R. P. B., and G.R.B. were responsible for conception and design; K. A., D. A. C., R. P. B., M. A. J., E. D. C., E. J., and A. G. performed experiments; T. D., G. D. A., G. R. B., and W. P. D. contributed to analysis and interpretation; and W. P. D, D. A. C., R. P. B., M. A. J., E. D. C., E. J., T. D., K. A., A. G., A. K., A.S., and G. R. B. drafted the manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. P. B. received personal fees from Actelion and from Mallinckrodt during the conduct of the study. None declared (W. P. D., D. A. C., M. A. J., E. D. C., E. J., G. D. A., T. D., K. A., A. G., A. K., A. S., G. R. B.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors are grateful for the support of the patients with sarcoidosis and nursing personnel for this investigation.
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
The contents of this article are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
FUNDING/SUPPORT: The publication was supported in part by CTSA award UL1 TR002243 from the 10.13039/100006108 National Center for Advancing Translational Sciences (G. R. B.); R01 HL117074 (W. P. D.); 10.13039/100004319 Pfizer Global Medical Grant Program 53232269; and the Pierce Foundation. | AZITHROMYCIN ANHYDROUS, ETHAMBUTOL HYDROCHLORIDE, LEVOFLOXACIN, RIFABUTIN | DrugsGivenReaction | CC BY-NC-ND | 33387486 | 18,762,907 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Leukopenia'. | Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis.
A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.
The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.
In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.
The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).
Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.
Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1,2 Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3,4
Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5, 6, 7 In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7, 8, 9 Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8 as well as following administration of antimycobacterial therapy to patients with this disease.10 The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10,11 Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11 A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12 We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease.
Patients and Methods
Trial Design and Objectives
This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses.
Protocol Development and Oversight
The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13 This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen.
Interventions
Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269).
Population Eligibility and Randomization
Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1 Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least 5% on serial measurements over 24 months; (2) radiographic progression in chest imaging on side-by-side comparison; or (3) decline in dyspnea score, as measured by using the Transition Dyspnea Index. Prior to randomization, participants were assessed for peripheral immune responses to ESAT-6 or evidence of peripheral anergy as defined by absence of responses to phytohemagglutinin. If either of those conditions were present, the subject was enrolled. Finally, participants were required to have evidence of parenchymal or nodal disease on chest radiograph. Site-specific pulmonologists who were unaffiliated with the CLEAR trial read all site-specific lung function tests.
Sample size was calculated for the primary end point: change from baseline of FVC percent predicted. Using data from participants with chronic pulmonary sarcoidosis treated with infliximab,14 we obtained the SD of 7.7 for the primary end point. A sample size of 51 completed participants per arm was needed to have 90% power to detect a 5% difference in change of FVC percent predicted from baseline.
The major exclusion criteria were as follows:(1) Inability to obtain consent.
(2) Age < 18 years.
(3) Female participants of childbearing potential not willing to use one of the following methods of birth control for the duration of the study and 90 days following study completion: condoms, sponge, foams, jellies, diaphragm, nonhormonal intrauterine device, a vasectomized sole partner, or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test result at screening visit was required if the female subject was of childbearing potential.
(4) FVC predicted value < 45%.
(5) End-stage fibrotic pulmonary disease.
(6) Significant underlying liver disease.
(7) Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
(8) Allergy or intolerance to albuterol.
(9) Poor venous access for obtaining blood samples.
(10) History of active TB, close contact with a person with active TB within the 6 months prior to the screening visit, or a positive purified protein derivative skin test result.
(11) Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation (eg, respiratory, cardiac, neurologic, musculoskeletal, or seizure disorders).
(12) Use of an investigational drug within 30 days prior to screening or within five half-lives of the agent, whichever is longer.
(13) Currently receiving > 40 mg of prednisone.
(14) Alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal.
(15) Leukopenia, as defined by a WBC count < 3.0 cells/mm3 or absolute neutrophil count < 1,000/μL.
(16) Breastfeeding.
(17) Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis.
(18) If the patient is on immunomodulators, they must be on a regimen for 3 months or longer and on a stable dose for > 4 weeks.
(19) Family or personal history of long QT interval.
(20) Most recent nuclear medicine scan or echocardiogram (if performed) showing cardiac ejection fraction < 35%.
(21) Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotic, antiretroviral, or antifungal agents within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis.
(22) Any significant finding in the patient’s medical history or physical or psychiatric examination prior to or following randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol.
(23) Taking medications that, in the opinion of the investigator, would affect patient safety when taken with the antibiotics of the CLEAR regimen.
(24) History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit.
Patients were assigned to receive the CLEAR or placebo regimen by using a block randomization stratified according to site and use of prednisone ≥ 10 mg or not. Randomization lists were generated and distributed to site pharmacies by a statistician at Vanderbilt University Medical Center not associated with the study.
Measurement of Treatment Completion
Patients were requested to bring all remaining doses of every trial drug to each visit for pill counts. Treatment completion for the per-protocol analysis was defined as administration of at least 90% of the doses within 16 weeks.
Measurement of Safety During Treatment
At each follow-up visit, participants were questioned and examined for adverse events. Suspected adverse events were investigated, managed, and reported according to a standardized protocol. Information about suspected adverse events was reviewed and graded by the site-specific principal investigator and clinical coordinator. The severity of adverse events was judged according to the Common Toxicity Criteria for Adverse Events version 4.0. The events were categorized as follows: an adverse event that was not related to a trial drug; an adverse event of grade 1 or 2 that was related to a trial drug (not serious); an adverse event of grade 3 or 4 that was related to a trial drug (generally considered to lead to trial drug discontinuation if related to a trial drug); or a grade 5 event (death) that was related to a trial drug. Each adverse event resulting in organ impairment, hospitalization, or death was defined as a serious adverse event (SAE). An SAE was reported and reviewed by the institutional review board, as well as the four-member Data Safety Monitoring Board. The board provided oversight regarding safety for continuation of the study.
Oversight
This trial was approved by the Vanderbilt University Human Research Protection Program and by the institutional review board at each participating site. All the authors vouch for the accuracy and completeness of the data and analyses presented and for the compliance of the trial to the protocol.
Statistical Analysis
This randomized Phase II clinical trial was conducted to determine if CLEAR elicits a statistically significant (two-sided value P < .05) improvement in respiratory performance, the 6MWD, SGRQ, and immune responses against ESAT-6. Ninety-seven patients were randomized to treatment from May 5, 2014, to December 13, 2018, of whom 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were cleaned and locked for final analysis on April 18, 2019. The primary end point was baseline to 16-week change in preinhaler FVC as percent predicted. We defined the 16-week postrandomization FVC percent predicted value measurement as the value closest to 16 weeks from randomization within a window of 12 to 20 weeks from randomization.
The primary comparison between the CLEAR and placebo arms was conducted on an intention-to-treat (as randomized) basis among patients with both baseline and 16-week outcomes (N = 97). Unless otherwise stated, mean, SE, and comparative P values were estimates with multiple imputation using predictive mean matching with aregImpute, as previously described.15,16 The multiple imputation data sets were summarized according to Rubin’s rules.17 Unless otherwise noted, figures represent the mean change score ± the SE computed by using Rubin’s rules for imputed data. Change scores for secondary end points were compared by using the linear model formulation of the two-sample test between groups over 100 imputed data sets. The paired Student t test for multiply imputed data was used to compare baseline and 16-week change scores within each treatment group at 8 and 16 weeks. All analyses were repeated for a per-protocol population of patients (n = 72). Analysis of ESAT-6 and adverse events was not based on imputed data. The ESAT-6 analysis was the only within-group comparison and was conducted by using a Student paired t test, comparing baseline with 16-week values within their randomization cohort. The number of subjects experiencing an SAE and separately an adverse event (adverse events not including SAEs) was compared between treatment arms by using the paired or unpaired Student t test.
Results
Trial Participants
We screened 446 potential patients from May 2014 through December 2018, of whom 97 were enrolled and randomized to treatment (Fig 1). The most common reasons for exclusion from study participation were as follows: (1) significant comorbid conditions; (2) a history of a drug interaction between one of the CLEAR antibiotics with a medication that the patient was currently receiving; (3) patient declined to participate; (4) pulmonary hypertension treatment; (5) concerns for noncompliance with study visits; and (6) Scadding stage IV fibrosis detected on a chest radiograph.Figure 1 Consort Diagram of Phase IIB investigation of the efficacy of antimycobacterial therapy against progressive pulmonary sarcoidosis. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; LTBI = latent TB infection.
The demographic and clinical characteristics of all study participants according to their randomization group are shown in Table 1. Of the 97 enrolled subjects, baseline characteristics were well balanced across treatment arms. Approximately one-half of the population (n = 50 [52%]) was female, and the majority were White (n = 68 [70%]), with approximately one-third African American (n = 28 [29%]). A possible balance exception was sex (59% women in the placebo group and 44% women in the CLEAR group). Although not a planned analysis, analysis of covariance of sex (P = .996) with treatment group (P = .903) on nonimputed data, as with their interaction (P = .678), suggests no confounding by sex.Table 1 Patient Demographic Characteristics According to Therapeutic Regimen
Characteristic CLEAR Placebo Combined
(n = 49) (n = 48) (N = 97)
Age, mean ± SD, y 54.5 ± 9.8 54.5 ± 9.8 54.5 ± 10
Sex
Male 20 (41%) 27 (56%) 47 (48%)
Female 29 (59%) 21 (44%) 50 (52%)
Race
African American 15 (31%) 13 (27%) 28 (29%)
White 34 (69%) 34 (71%) 68 (70%)
Hawaiian or Pacific Islander 0 (0) 1 (2%) 1 (1%)
Ethnicity
Non-Hispanic/nor Latino 48 (98%) 46 (96%) 94 (97%)
Hispanic/Latino 1 (2%) 2 (4%) 3 (3%)
Baseline end points
Preinhaler FVC % 77.3 ± 13.7 75.5 ± 14.5 75.4 ± 14.1
6-min walk test, ma 416.2 ± 140.7 416.4 ± 105.2 416.3 ± 123.5
SGRQ activityb 57.7 ± 23.2 55.5 ± 24.5 56.6 ± 23.8
SGRQ impactb 34.8 ± 22.2 32.9 ± 19.8 33.8 ± 20.9
SGRQ symptomsb 53.9 ± 23.8 50.5 ± 19.3 52.2 ± 21.7
SGRQ totalb 44.9 ± 21.1 42.7 ± 18.7 43.8 ± 19.9
Immunosuppression
Patients on prednisone (mean dosage) 23 (47%) (10 mg) 19 (40%) (10 mg) 42 (43%) (10 mg)
Patients on a DMA 19 (39%) 17 (35%) 36 (37%)
Patients on a biologic agent 1 (2%) 1 (2%) 2 (4%)
Patients on prednisone plus a DMA or biologic agent 10 (20%) 6 (13%) 16 (16%)
Patients on any combination of prednisone, DMA, or biologic agent 11 (22%) 8 (17%) 19 (20%)
ESAT-6 positivity
Yes 39 (80%) 36 (75%) 75 (77%)
Equivocal 10 (20%) 12 (25%) 25 (23%)
CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; DMA = disease-modifying agent; ESAT-6 = early secreted antigenic target of 6 kDa.
a N = 48 for CLEAR and placebo groups.
b N = 48 and N = 47, for CLEAR and placebo groups, respectively.
The clinical data were analyzed via intention-to-treat and per protocol. No subjects were excluded from the intention-to-treat analysis. In the per-protocol analysis, 25 (12 in the active arm and 13 in the placebo arm) of the 97 patients were excluded because of failure to take > 4 weeks of the prescribed regimen (CLEAR, n = 8; placebo, n = 4), alteration in clinical immunosuppressive regimen while on study drugs (CLEAR, n = 1; placebo, n = 3), initiation of non-study antibiotics during study participation (CLEAR, n = 1; placebo, n = 3), and found to be receiving antibiotics with antimycobacterial therapy, such as trimethoprim-sulfamethoxazole, at the time of enrollment (CLEAR, n = 2; placebo, n = 3). The remaining 72 subjects were included in the per-protocol analysis.
Efficacy
In the intention-to-treat analysis, there were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between the CLEAR and placebo groups (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64) (Fig 2A, Table 2). Eight-eight patients experienced follow-up during the 12- to 20-week postrandomization window. Median (interquartile range) and mean ± SD of time to the date of FVC percent measurement was 17 (16.1-18) weeks and 17.5 ± 1.9 weeks, respectively. Time to primary end point measurement was equivalent between treatment groups, with a median (interquartile range) of 17 (16.2-18) weeks for placebo and 17.2 (16.2-18.0) weeks for CLEAR II patients. Mean ± SD values were 17.5 ± 1.9 and 17.4 ± 1.8. Evaluation of other physiological parameters, such as 6MWD (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = .91) revealed no statistically significant differences (Fig 2B). A negative change in the SGRQ score reflects an improvement in quality of life. The SRGQ did reveal statistically and clinically significant differences in favor of the placebo group (placebo, –7.97; CLEAR II, –1.52; P = .028, minimal clinically important difference = 4.0).Figure 2 A-B, Graphic depiction of intention-to-treat assessment of physiological parameters such as FVC and 6-min walk distance in 97 subjects with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, There were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between 49 CLEAR and 48 placebo subjects (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64). B, Evaluation of 6-min walk distance (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = 0.91) revealed no statistically significant difference. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Table 2 Physiological and Qualitative End Point Analyses
Variable Placebo CLEAR P Value
Intent-to-treat population
Preinhaler FVC % 0.02 ± 1.47 –1.06 ± 1.85 .640
6-min walk distance 12.40 ± 12.35 9.78 ± 19.31 .908
SGRQ activity –7.15 ± 3.28 –0.96 ± 2.87 .162
SGRQ impact –7.45 ± 2.64 –0.61 ± 2.78 .057
SGRQ symptoms –10.15 ± 3.45 –5.62 ± 3.22 .331
SGRQ total –7.97 ± 2.01 –1.52 ± 2.17 .028
Per-protocol group
Preinhaler FVC % 0.42 ± 1.48 –0.74 ± 1.75 .616
6-min walk distance 6.27 ± 11.99 36.35 ± 22.32 .242
SGRQ activity –4.25 ± 2.39 –1.45 ± 2.91 .458
SGRQ impact –7.97 ± 2.51 –1,10 ± 2.62 .061
SGRQ symptoms –9.78 ± 3.60 –8.07 ± 3.39 .730
SGRQ total –6.97 ± 2.13 –2.32 ± 2.32 .141
Imputed mean ± SE of baseline to 16-week differences in measurements. P values are from imputation-based two-sample Student t test. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; SGRQ = St. George’s Respiratory Questionnaire.
In the per-protocol analysis, 72 subjects were analyzed following removal of 25 patients prior to data analysis due to factors outlined in the protocol. Comparison of baseline vs week 16 end points of the remaining 72 patients revealed that there were no statistically differences in the primary end point (the change from baseline in percent predicted FVC) between 37 CLEAR-treated patients compared with 35 patients receiving placebo (CLEAR –0.74% vs placebo 0.42%; P = .62) (Fig 3A, Table 2). Evaluation of other physiological and qualitative end points revealed no significant differences; for example, there were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = .242) (Fig 3B). The SGRQ also revealed no significant differences in the total score between the groups (placebo, –6.9; CLEAR, –2.3; imputed two-sample Student t test, P = .14). CLEAR-treated patients had less improvement in activity, impact, and symptoms compared with patients receiving placebo.Figure 3 A-B, Graphic depiction of per-protocol assessment of physiologic parameters, such as FVC and placebo in 97 patients with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, Comparison of baseline vs week 16 end points of 72 subjects revealed that there were no statistically differences in the primary end point (change from baseline in percent predicted FVC) between 37 CLEAR subjects compared with 35 placebo subjects (CLEAR –0.74% vs placebo 0.42%; imputed two-sample Student t test, P = .62). B, Evaluation of 6-min walk distance revealed no significant difference among patients randomized to the CLEAR or the placebo regimen (36.4 m vs 6.3 m; imputed two-sample Student t test, P = .242). CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Although there was no significant baseline difference in ESAT-6-specific spot-forming units between the two groups (unpaired Student t test, P = .48) (Fig 4A), there was a significant difference in the spot-forming units following 16 weeks of therapy. There was no significant change in 38 subjects randomized to receive placebo (paired Student t test, P = .26) (Fig 4B); however, a significant decline in the ESAT-6 spot-forming units among the 31 patients randomized to the CLEAR regimen (paired Student t test, P = .0003) (Fig 4C). Only subjects for whom baseline and 16-week values were available were included in this analysis.Figure 4 Comparison of ESAT-6 immune responses at baseline (n = 69 subjects) (A), as well as baseline to 16 weeks among patients with sarcoidosis randomized to either the placebo (n = 38 subjects) (B) or CLEAR (n = 31 subjects) (C) regimen. ESAT-6 = early secreted antigenic target of 6 kDa; NS = not significant; PBMC = peripheral blood mononuclear cells; SFU = spot-forming units.
Safety
At each follow-up visit, participants were evaluated for adverse events. A total of 75 adverse events were noted in 39 subjects (e-Table 1). Any adverse event resulting in organ impairment, hospitalization, or death was defined as an SAE. The number of SAEs was similar for CLEAR (n = 4) and placebo (n = 3) (P = .72) (Table 3). Three of the four SAEs in the CLEAR cohort were believed to be related to study drugs; none was believed to be related in the placebo cohort. There were no deaths in this trial.Table 3 SAEs Throughout the Study
SAE Number Event Group Institution Date Anticipated Caused by Therapy
1 Leukopenia Active Cincinnati 08/14/2016 Yes Probable
2 Pneumonia Active Cincinnati 11/06/2014 Yes Probable
3 Neurosarcoidosis Active Vanderbilt 12/28/2016 No Not related
4 Hypotension Active AMC 01/29/2018 Yes Probable
5 Sepsis from abscess Placebo Cleveland 07/18/2017 No Not related
6 Postoperative infection Placebo Cleveland 11/14/2014 No Unlikely
7 Pneumonia Placebo Cleveland 06/04/2018 No Not related
AMC = Albany Medical College; SAE = severe adverse event.
Discussion
In this randomized, double-blind, placebo-controlled trial of CLEAR therapy, we observed no benefit from the study intervention on pulmonary function, for both the intention-to-treat and per-protocol analyses. Most secondary end points, such as 6MWD and SGRQ, showed no significant improvement from CLEAR, and SGRQ was worse at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated subjects, but no change was observed among those randomized to receive placebo (Figs 3, 4).
Although viable mycobacteria have been proposed to be causative agents for sarcoidosis, the current study provides no evidence to support that hypothesis. The current results are discordant from a randomized trial in which CLEAR therapy was beneficial for cutaneous sarcoidosis, and they also diverge from an uncontrolled report of CLEAR therapy.10,11 One explanation for the failure of CLEAR therapy is that the underlying hypothesis regarding the cause of sarcoidosis is incorrect. This explanation accords with the failure of prior studies to culture mycobacteria from sarcoidosis tissues.18,19
Other explanations for the failure of CLEAR therapy should also be considered. The inclusion criteria were designed to enroll a population with actively progressing sarcoidosis, but the precision of the longitudinal data supporting progression, and the long time window for demonstrating progression, are both problematic and may have biased the study population to include patients with relatively stable, adequately controlled disease.20 Progression in the placebo group on stable therapy would not be expected in a 16-week time frame. Active withdrawal of anti-sarcoidosis medications may be necessary to uncover relative treatment benefits if the effect size is modest, but this study required stable dosing throughout the treatment period. It is also possible that the treatment duration was too short to discern efficacy of therapy; medications such as methotrexate require up to 6 months to effect benefit in pulmonary sarcoidosis.21 Antibiotic therapy may not result in improved FVC; one study noted that these patients may continue to experience an FVC decline, but it occurs at a significantly lower rate than patients who were not successfully treated.22 Finally, FVC may be an insensitive marker of treatment effect; it has previously been shown to correlate poorly with symptoms and with chest imaging.23,24 However, the absence of any observable clinical benefits argues that the end point chosen here is likely not the cause of the negative result.
Immune responses against mycobacterial antigens, such as ESAT-6 and katG, are present in patients with active sarcoidosis disease.8,25,26 Independent investigators found that, using the ELISpot assay, antimycobacterial responses disappear with clinical resolution of sarcoidosis.8 Immune responses against ESAT-6 have also been detected with active or latent TB, as well as other nontuberculous mycobacteria infections27, 28, 29; these responses decline with effective antimycobacterial therapy.30, 31, 32 A significant decline in the ESAT-6 immune responses among subjects randomized to receive CLEAR (but not placebo) is provocative and of uncertain significance. It is unlikely that the decrease in ESAT-6 response in the CLEAR group is due to an immunosuppressant effect of one or more antibiotics in the treatment regimen because we previously reported improved immune function, including enhanced T-cell proliferative capacity and increased IL-2 and interferon-γ secretion, as well as augmented JAK-STAT signaling from sarcoidosis CD4+ T cells, following completion of the CLEAR regimen.11 The improvement in cellular immunity with CLEAR treatment of sarcoidosis could result in the augmented capacity to remove pathogenic microbial antigens such as ESAT-6. In addition, because the removal of microbial antigens such as ESAT-6 during treatment of mycobacterial infection reduces expression of profibrotic cytokines such as IL-17A, this mechanism may also mitigate the development of lung fibrosis during the treatment of sarcoidosis. The discrepancy between measurable declines in a virulence factor associated with active mycobacterial replication (ESAT-6) and the negative results of the current study remain unexplained.
It may be that mycobacterial antigens are important initial triggers of some cases of sarcoidosis, as suggested by persistence of mycobacterial antigens in sarcoidosis tissues,7 but viable infection is not integral to the perpetuation or progression of the disease. Also, because the study design did not obtain any samples to exclude the presence of infection in the subjects, it remains possible that the effects of CLEAR resulted in changes in the microbiome, which could then affect immune responses by changing the presence of microbial antigens. Future investigation regarding the impact of the CLEAR regimen on preventing further lung deterioration is warranted.
The current study did have some limitations. The number of subjects was relatively small. Twenty-five of the 97 patients were excluded from the per-protocol analysis, representing approximately 26% of the enrolled subjects. Twelve of those subjects (CLEAR, n = 8; placebo, n = 4) were excluded due to taking < 4 weeks of study medications, making it more difficult to assess the impact of 16 weeks of CLEAR therapy on the primary and secondary end points. Due to the pill burden and toxicities associated with a four-drug regimen, difficulty adhering to antimycobacterial therapy is well documented.33, 34, 35 Toxicities, such as myalgias and arthralgias from azithromycin and levofloxacin, as well as fatigue from rifabutin, may have affected the SGRQ score, masking our ability to clearly delineate an anti-sarcoidosis effect. Higher SGRQ scores were noted among CLEAR-treated patients experiencing these toxicities. Another limitation is the failure to include patients with disease for < 1 year. We did not include patients within 1 year of diagnosis because it was believed that differentiation of drug efficacy from spontaneous resolution would be too difficult. However, improvement in lung function among patients with TB is more likely if patients are < 40 years of age and do not have chronic sequelae.36 Future sarcoidosis clinical investigations should include patients within 1 year of their diagnosis, longer follow-up period assessment for potential steroid-sparing effect, and CT or PET scans. Several studies have shown that increased activity according to a PET scan is a useful predictor of treatment-responsive pulmonary sarcoidosis.37,38 PET scanning was not included in the current study because the information at time of study implementation was incomplete, and the cost of this as an exploratory analysis was prohibitive.
Conclusions
In a cohort of patients with progressive pulmonary sarcoidosis, the CLEAR therapy did not result in significant improvement in percent predicted FVC but, instead, was associated with significant declines in ESAT-6-specific immune responses.
Supplementary Data
e-Online Data
Acknowledgments
Author contributions: W. P. D. had full access to all the data following study completion and assumes full responsibility for the integrity of the data and the accuracy of the data analysis. W. P. D., D. A. C., R. P. B., and G.R.B. were responsible for conception and design; K. A., D. A. C., R. P. B., M. A. J., E. D. C., E. J., and A. G. performed experiments; T. D., G. D. A., G. R. B., and W. P. D. contributed to analysis and interpretation; and W. P. D, D. A. C., R. P. B., M. A. J., E. D. C., E. J., T. D., K. A., A. G., A. K., A.S., and G. R. B. drafted the manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. P. B. received personal fees from Actelion and from Mallinckrodt during the conduct of the study. None declared (W. P. D., D. A. C., M. A. J., E. D. C., E. J., G. D. A., T. D., K. A., A. G., A. K., A. S., G. R. B.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors are grateful for the support of the patients with sarcoidosis and nursing personnel for this investigation.
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
The contents of this article are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
FUNDING/SUPPORT: The publication was supported in part by CTSA award UL1 TR002243 from the 10.13039/100006108 National Center for Advancing Translational Sciences (G. R. B.); R01 HL117074 (W. P. D.); 10.13039/100004319 Pfizer Global Medical Grant Program 53232269; and the Pierce Foundation. | AZITHROMYCIN ANHYDROUS, ETHAMBUTOL HYDROCHLORIDE, LEVOFLOXACIN, RIFABUTIN | DrugsGivenReaction | CC BY-NC-ND | 33387486 | 18,762,907 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis.
A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.
The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.
In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.
The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).
Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.
Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1,2 Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3,4
Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5, 6, 7 In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7, 8, 9 Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8 as well as following administration of antimycobacterial therapy to patients with this disease.10 The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10,11 Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11 A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12 We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease.
Patients and Methods
Trial Design and Objectives
This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses.
Protocol Development and Oversight
The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13 This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen.
Interventions
Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269).
Population Eligibility and Randomization
Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1 Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least 5% on serial measurements over 24 months; (2) radiographic progression in chest imaging on side-by-side comparison; or (3) decline in dyspnea score, as measured by using the Transition Dyspnea Index. Prior to randomization, participants were assessed for peripheral immune responses to ESAT-6 or evidence of peripheral anergy as defined by absence of responses to phytohemagglutinin. If either of those conditions were present, the subject was enrolled. Finally, participants were required to have evidence of parenchymal or nodal disease on chest radiograph. Site-specific pulmonologists who were unaffiliated with the CLEAR trial read all site-specific lung function tests.
Sample size was calculated for the primary end point: change from baseline of FVC percent predicted. Using data from participants with chronic pulmonary sarcoidosis treated with infliximab,14 we obtained the SD of 7.7 for the primary end point. A sample size of 51 completed participants per arm was needed to have 90% power to detect a 5% difference in change of FVC percent predicted from baseline.
The major exclusion criteria were as follows:(1) Inability to obtain consent.
(2) Age < 18 years.
(3) Female participants of childbearing potential not willing to use one of the following methods of birth control for the duration of the study and 90 days following study completion: condoms, sponge, foams, jellies, diaphragm, nonhormonal intrauterine device, a vasectomized sole partner, or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test result at screening visit was required if the female subject was of childbearing potential.
(4) FVC predicted value < 45%.
(5) End-stage fibrotic pulmonary disease.
(6) Significant underlying liver disease.
(7) Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
(8) Allergy or intolerance to albuterol.
(9) Poor venous access for obtaining blood samples.
(10) History of active TB, close contact with a person with active TB within the 6 months prior to the screening visit, or a positive purified protein derivative skin test result.
(11) Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation (eg, respiratory, cardiac, neurologic, musculoskeletal, or seizure disorders).
(12) Use of an investigational drug within 30 days prior to screening or within five half-lives of the agent, whichever is longer.
(13) Currently receiving > 40 mg of prednisone.
(14) Alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal.
(15) Leukopenia, as defined by a WBC count < 3.0 cells/mm3 or absolute neutrophil count < 1,000/μL.
(16) Breastfeeding.
(17) Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis.
(18) If the patient is on immunomodulators, they must be on a regimen for 3 months or longer and on a stable dose for > 4 weeks.
(19) Family or personal history of long QT interval.
(20) Most recent nuclear medicine scan or echocardiogram (if performed) showing cardiac ejection fraction < 35%.
(21) Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotic, antiretroviral, or antifungal agents within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis.
(22) Any significant finding in the patient’s medical history or physical or psychiatric examination prior to or following randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol.
(23) Taking medications that, in the opinion of the investigator, would affect patient safety when taken with the antibiotics of the CLEAR regimen.
(24) History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit.
Patients were assigned to receive the CLEAR or placebo regimen by using a block randomization stratified according to site and use of prednisone ≥ 10 mg or not. Randomization lists were generated and distributed to site pharmacies by a statistician at Vanderbilt University Medical Center not associated with the study.
Measurement of Treatment Completion
Patients were requested to bring all remaining doses of every trial drug to each visit for pill counts. Treatment completion for the per-protocol analysis was defined as administration of at least 90% of the doses within 16 weeks.
Measurement of Safety During Treatment
At each follow-up visit, participants were questioned and examined for adverse events. Suspected adverse events were investigated, managed, and reported according to a standardized protocol. Information about suspected adverse events was reviewed and graded by the site-specific principal investigator and clinical coordinator. The severity of adverse events was judged according to the Common Toxicity Criteria for Adverse Events version 4.0. The events were categorized as follows: an adverse event that was not related to a trial drug; an adverse event of grade 1 or 2 that was related to a trial drug (not serious); an adverse event of grade 3 or 4 that was related to a trial drug (generally considered to lead to trial drug discontinuation if related to a trial drug); or a grade 5 event (death) that was related to a trial drug. Each adverse event resulting in organ impairment, hospitalization, or death was defined as a serious adverse event (SAE). An SAE was reported and reviewed by the institutional review board, as well as the four-member Data Safety Monitoring Board. The board provided oversight regarding safety for continuation of the study.
Oversight
This trial was approved by the Vanderbilt University Human Research Protection Program and by the institutional review board at each participating site. All the authors vouch for the accuracy and completeness of the data and analyses presented and for the compliance of the trial to the protocol.
Statistical Analysis
This randomized Phase II clinical trial was conducted to determine if CLEAR elicits a statistically significant (two-sided value P < .05) improvement in respiratory performance, the 6MWD, SGRQ, and immune responses against ESAT-6. Ninety-seven patients were randomized to treatment from May 5, 2014, to December 13, 2018, of whom 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were cleaned and locked for final analysis on April 18, 2019. The primary end point was baseline to 16-week change in preinhaler FVC as percent predicted. We defined the 16-week postrandomization FVC percent predicted value measurement as the value closest to 16 weeks from randomization within a window of 12 to 20 weeks from randomization.
The primary comparison between the CLEAR and placebo arms was conducted on an intention-to-treat (as randomized) basis among patients with both baseline and 16-week outcomes (N = 97). Unless otherwise stated, mean, SE, and comparative P values were estimates with multiple imputation using predictive mean matching with aregImpute, as previously described.15,16 The multiple imputation data sets were summarized according to Rubin’s rules.17 Unless otherwise noted, figures represent the mean change score ± the SE computed by using Rubin’s rules for imputed data. Change scores for secondary end points were compared by using the linear model formulation of the two-sample test between groups over 100 imputed data sets. The paired Student t test for multiply imputed data was used to compare baseline and 16-week change scores within each treatment group at 8 and 16 weeks. All analyses were repeated for a per-protocol population of patients (n = 72). Analysis of ESAT-6 and adverse events was not based on imputed data. The ESAT-6 analysis was the only within-group comparison and was conducted by using a Student paired t test, comparing baseline with 16-week values within their randomization cohort. The number of subjects experiencing an SAE and separately an adverse event (adverse events not including SAEs) was compared between treatment arms by using the paired or unpaired Student t test.
Results
Trial Participants
We screened 446 potential patients from May 2014 through December 2018, of whom 97 were enrolled and randomized to treatment (Fig 1). The most common reasons for exclusion from study participation were as follows: (1) significant comorbid conditions; (2) a history of a drug interaction between one of the CLEAR antibiotics with a medication that the patient was currently receiving; (3) patient declined to participate; (4) pulmonary hypertension treatment; (5) concerns for noncompliance with study visits; and (6) Scadding stage IV fibrosis detected on a chest radiograph.Figure 1 Consort Diagram of Phase IIB investigation of the efficacy of antimycobacterial therapy against progressive pulmonary sarcoidosis. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; LTBI = latent TB infection.
The demographic and clinical characteristics of all study participants according to their randomization group are shown in Table 1. Of the 97 enrolled subjects, baseline characteristics were well balanced across treatment arms. Approximately one-half of the population (n = 50 [52%]) was female, and the majority were White (n = 68 [70%]), with approximately one-third African American (n = 28 [29%]). A possible balance exception was sex (59% women in the placebo group and 44% women in the CLEAR group). Although not a planned analysis, analysis of covariance of sex (P = .996) with treatment group (P = .903) on nonimputed data, as with their interaction (P = .678), suggests no confounding by sex.Table 1 Patient Demographic Characteristics According to Therapeutic Regimen
Characteristic CLEAR Placebo Combined
(n = 49) (n = 48) (N = 97)
Age, mean ± SD, y 54.5 ± 9.8 54.5 ± 9.8 54.5 ± 10
Sex
Male 20 (41%) 27 (56%) 47 (48%)
Female 29 (59%) 21 (44%) 50 (52%)
Race
African American 15 (31%) 13 (27%) 28 (29%)
White 34 (69%) 34 (71%) 68 (70%)
Hawaiian or Pacific Islander 0 (0) 1 (2%) 1 (1%)
Ethnicity
Non-Hispanic/nor Latino 48 (98%) 46 (96%) 94 (97%)
Hispanic/Latino 1 (2%) 2 (4%) 3 (3%)
Baseline end points
Preinhaler FVC % 77.3 ± 13.7 75.5 ± 14.5 75.4 ± 14.1
6-min walk test, ma 416.2 ± 140.7 416.4 ± 105.2 416.3 ± 123.5
SGRQ activityb 57.7 ± 23.2 55.5 ± 24.5 56.6 ± 23.8
SGRQ impactb 34.8 ± 22.2 32.9 ± 19.8 33.8 ± 20.9
SGRQ symptomsb 53.9 ± 23.8 50.5 ± 19.3 52.2 ± 21.7
SGRQ totalb 44.9 ± 21.1 42.7 ± 18.7 43.8 ± 19.9
Immunosuppression
Patients on prednisone (mean dosage) 23 (47%) (10 mg) 19 (40%) (10 mg) 42 (43%) (10 mg)
Patients on a DMA 19 (39%) 17 (35%) 36 (37%)
Patients on a biologic agent 1 (2%) 1 (2%) 2 (4%)
Patients on prednisone plus a DMA or biologic agent 10 (20%) 6 (13%) 16 (16%)
Patients on any combination of prednisone, DMA, or biologic agent 11 (22%) 8 (17%) 19 (20%)
ESAT-6 positivity
Yes 39 (80%) 36 (75%) 75 (77%)
Equivocal 10 (20%) 12 (25%) 25 (23%)
CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; DMA = disease-modifying agent; ESAT-6 = early secreted antigenic target of 6 kDa.
a N = 48 for CLEAR and placebo groups.
b N = 48 and N = 47, for CLEAR and placebo groups, respectively.
The clinical data were analyzed via intention-to-treat and per protocol. No subjects were excluded from the intention-to-treat analysis. In the per-protocol analysis, 25 (12 in the active arm and 13 in the placebo arm) of the 97 patients were excluded because of failure to take > 4 weeks of the prescribed regimen (CLEAR, n = 8; placebo, n = 4), alteration in clinical immunosuppressive regimen while on study drugs (CLEAR, n = 1; placebo, n = 3), initiation of non-study antibiotics during study participation (CLEAR, n = 1; placebo, n = 3), and found to be receiving antibiotics with antimycobacterial therapy, such as trimethoprim-sulfamethoxazole, at the time of enrollment (CLEAR, n = 2; placebo, n = 3). The remaining 72 subjects were included in the per-protocol analysis.
Efficacy
In the intention-to-treat analysis, there were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between the CLEAR and placebo groups (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64) (Fig 2A, Table 2). Eight-eight patients experienced follow-up during the 12- to 20-week postrandomization window. Median (interquartile range) and mean ± SD of time to the date of FVC percent measurement was 17 (16.1-18) weeks and 17.5 ± 1.9 weeks, respectively. Time to primary end point measurement was equivalent between treatment groups, with a median (interquartile range) of 17 (16.2-18) weeks for placebo and 17.2 (16.2-18.0) weeks for CLEAR II patients. Mean ± SD values were 17.5 ± 1.9 and 17.4 ± 1.8. Evaluation of other physiological parameters, such as 6MWD (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = .91) revealed no statistically significant differences (Fig 2B). A negative change in the SGRQ score reflects an improvement in quality of life. The SRGQ did reveal statistically and clinically significant differences in favor of the placebo group (placebo, –7.97; CLEAR II, –1.52; P = .028, minimal clinically important difference = 4.0).Figure 2 A-B, Graphic depiction of intention-to-treat assessment of physiological parameters such as FVC and 6-min walk distance in 97 subjects with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, There were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between 49 CLEAR and 48 placebo subjects (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64). B, Evaluation of 6-min walk distance (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = 0.91) revealed no statistically significant difference. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Table 2 Physiological and Qualitative End Point Analyses
Variable Placebo CLEAR P Value
Intent-to-treat population
Preinhaler FVC % 0.02 ± 1.47 –1.06 ± 1.85 .640
6-min walk distance 12.40 ± 12.35 9.78 ± 19.31 .908
SGRQ activity –7.15 ± 3.28 –0.96 ± 2.87 .162
SGRQ impact –7.45 ± 2.64 –0.61 ± 2.78 .057
SGRQ symptoms –10.15 ± 3.45 –5.62 ± 3.22 .331
SGRQ total –7.97 ± 2.01 –1.52 ± 2.17 .028
Per-protocol group
Preinhaler FVC % 0.42 ± 1.48 –0.74 ± 1.75 .616
6-min walk distance 6.27 ± 11.99 36.35 ± 22.32 .242
SGRQ activity –4.25 ± 2.39 –1.45 ± 2.91 .458
SGRQ impact –7.97 ± 2.51 –1,10 ± 2.62 .061
SGRQ symptoms –9.78 ± 3.60 –8.07 ± 3.39 .730
SGRQ total –6.97 ± 2.13 –2.32 ± 2.32 .141
Imputed mean ± SE of baseline to 16-week differences in measurements. P values are from imputation-based two-sample Student t test. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; SGRQ = St. George’s Respiratory Questionnaire.
In the per-protocol analysis, 72 subjects were analyzed following removal of 25 patients prior to data analysis due to factors outlined in the protocol. Comparison of baseline vs week 16 end points of the remaining 72 patients revealed that there were no statistically differences in the primary end point (the change from baseline in percent predicted FVC) between 37 CLEAR-treated patients compared with 35 patients receiving placebo (CLEAR –0.74% vs placebo 0.42%; P = .62) (Fig 3A, Table 2). Evaluation of other physiological and qualitative end points revealed no significant differences; for example, there were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = .242) (Fig 3B). The SGRQ also revealed no significant differences in the total score between the groups (placebo, –6.9; CLEAR, –2.3; imputed two-sample Student t test, P = .14). CLEAR-treated patients had less improvement in activity, impact, and symptoms compared with patients receiving placebo.Figure 3 A-B, Graphic depiction of per-protocol assessment of physiologic parameters, such as FVC and placebo in 97 patients with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, Comparison of baseline vs week 16 end points of 72 subjects revealed that there were no statistically differences in the primary end point (change from baseline in percent predicted FVC) between 37 CLEAR subjects compared with 35 placebo subjects (CLEAR –0.74% vs placebo 0.42%; imputed two-sample Student t test, P = .62). B, Evaluation of 6-min walk distance revealed no significant difference among patients randomized to the CLEAR or the placebo regimen (36.4 m vs 6.3 m; imputed two-sample Student t test, P = .242). CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Although there was no significant baseline difference in ESAT-6-specific spot-forming units between the two groups (unpaired Student t test, P = .48) (Fig 4A), there was a significant difference in the spot-forming units following 16 weeks of therapy. There was no significant change in 38 subjects randomized to receive placebo (paired Student t test, P = .26) (Fig 4B); however, a significant decline in the ESAT-6 spot-forming units among the 31 patients randomized to the CLEAR regimen (paired Student t test, P = .0003) (Fig 4C). Only subjects for whom baseline and 16-week values were available were included in this analysis.Figure 4 Comparison of ESAT-6 immune responses at baseline (n = 69 subjects) (A), as well as baseline to 16 weeks among patients with sarcoidosis randomized to either the placebo (n = 38 subjects) (B) or CLEAR (n = 31 subjects) (C) regimen. ESAT-6 = early secreted antigenic target of 6 kDa; NS = not significant; PBMC = peripheral blood mononuclear cells; SFU = spot-forming units.
Safety
At each follow-up visit, participants were evaluated for adverse events. A total of 75 adverse events were noted in 39 subjects (e-Table 1). Any adverse event resulting in organ impairment, hospitalization, or death was defined as an SAE. The number of SAEs was similar for CLEAR (n = 4) and placebo (n = 3) (P = .72) (Table 3). Three of the four SAEs in the CLEAR cohort were believed to be related to study drugs; none was believed to be related in the placebo cohort. There were no deaths in this trial.Table 3 SAEs Throughout the Study
SAE Number Event Group Institution Date Anticipated Caused by Therapy
1 Leukopenia Active Cincinnati 08/14/2016 Yes Probable
2 Pneumonia Active Cincinnati 11/06/2014 Yes Probable
3 Neurosarcoidosis Active Vanderbilt 12/28/2016 No Not related
4 Hypotension Active AMC 01/29/2018 Yes Probable
5 Sepsis from abscess Placebo Cleveland 07/18/2017 No Not related
6 Postoperative infection Placebo Cleveland 11/14/2014 No Unlikely
7 Pneumonia Placebo Cleveland 06/04/2018 No Not related
AMC = Albany Medical College; SAE = severe adverse event.
Discussion
In this randomized, double-blind, placebo-controlled trial of CLEAR therapy, we observed no benefit from the study intervention on pulmonary function, for both the intention-to-treat and per-protocol analyses. Most secondary end points, such as 6MWD and SGRQ, showed no significant improvement from CLEAR, and SGRQ was worse at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated subjects, but no change was observed among those randomized to receive placebo (Figs 3, 4).
Although viable mycobacteria have been proposed to be causative agents for sarcoidosis, the current study provides no evidence to support that hypothesis. The current results are discordant from a randomized trial in which CLEAR therapy was beneficial for cutaneous sarcoidosis, and they also diverge from an uncontrolled report of CLEAR therapy.10,11 One explanation for the failure of CLEAR therapy is that the underlying hypothesis regarding the cause of sarcoidosis is incorrect. This explanation accords with the failure of prior studies to culture mycobacteria from sarcoidosis tissues.18,19
Other explanations for the failure of CLEAR therapy should also be considered. The inclusion criteria were designed to enroll a population with actively progressing sarcoidosis, but the precision of the longitudinal data supporting progression, and the long time window for demonstrating progression, are both problematic and may have biased the study population to include patients with relatively stable, adequately controlled disease.20 Progression in the placebo group on stable therapy would not be expected in a 16-week time frame. Active withdrawal of anti-sarcoidosis medications may be necessary to uncover relative treatment benefits if the effect size is modest, but this study required stable dosing throughout the treatment period. It is also possible that the treatment duration was too short to discern efficacy of therapy; medications such as methotrexate require up to 6 months to effect benefit in pulmonary sarcoidosis.21 Antibiotic therapy may not result in improved FVC; one study noted that these patients may continue to experience an FVC decline, but it occurs at a significantly lower rate than patients who were not successfully treated.22 Finally, FVC may be an insensitive marker of treatment effect; it has previously been shown to correlate poorly with symptoms and with chest imaging.23,24 However, the absence of any observable clinical benefits argues that the end point chosen here is likely not the cause of the negative result.
Immune responses against mycobacterial antigens, such as ESAT-6 and katG, are present in patients with active sarcoidosis disease.8,25,26 Independent investigators found that, using the ELISpot assay, antimycobacterial responses disappear with clinical resolution of sarcoidosis.8 Immune responses against ESAT-6 have also been detected with active or latent TB, as well as other nontuberculous mycobacteria infections27, 28, 29; these responses decline with effective antimycobacterial therapy.30, 31, 32 A significant decline in the ESAT-6 immune responses among subjects randomized to receive CLEAR (but not placebo) is provocative and of uncertain significance. It is unlikely that the decrease in ESAT-6 response in the CLEAR group is due to an immunosuppressant effect of one or more antibiotics in the treatment regimen because we previously reported improved immune function, including enhanced T-cell proliferative capacity and increased IL-2 and interferon-γ secretion, as well as augmented JAK-STAT signaling from sarcoidosis CD4+ T cells, following completion of the CLEAR regimen.11 The improvement in cellular immunity with CLEAR treatment of sarcoidosis could result in the augmented capacity to remove pathogenic microbial antigens such as ESAT-6. In addition, because the removal of microbial antigens such as ESAT-6 during treatment of mycobacterial infection reduces expression of profibrotic cytokines such as IL-17A, this mechanism may also mitigate the development of lung fibrosis during the treatment of sarcoidosis. The discrepancy between measurable declines in a virulence factor associated with active mycobacterial replication (ESAT-6) and the negative results of the current study remain unexplained.
It may be that mycobacterial antigens are important initial triggers of some cases of sarcoidosis, as suggested by persistence of mycobacterial antigens in sarcoidosis tissues,7 but viable infection is not integral to the perpetuation or progression of the disease. Also, because the study design did not obtain any samples to exclude the presence of infection in the subjects, it remains possible that the effects of CLEAR resulted in changes in the microbiome, which could then affect immune responses by changing the presence of microbial antigens. Future investigation regarding the impact of the CLEAR regimen on preventing further lung deterioration is warranted.
The current study did have some limitations. The number of subjects was relatively small. Twenty-five of the 97 patients were excluded from the per-protocol analysis, representing approximately 26% of the enrolled subjects. Twelve of those subjects (CLEAR, n = 8; placebo, n = 4) were excluded due to taking < 4 weeks of study medications, making it more difficult to assess the impact of 16 weeks of CLEAR therapy on the primary and secondary end points. Due to the pill burden and toxicities associated with a four-drug regimen, difficulty adhering to antimycobacterial therapy is well documented.33, 34, 35 Toxicities, such as myalgias and arthralgias from azithromycin and levofloxacin, as well as fatigue from rifabutin, may have affected the SGRQ score, masking our ability to clearly delineate an anti-sarcoidosis effect. Higher SGRQ scores were noted among CLEAR-treated patients experiencing these toxicities. Another limitation is the failure to include patients with disease for < 1 year. We did not include patients within 1 year of diagnosis because it was believed that differentiation of drug efficacy from spontaneous resolution would be too difficult. However, improvement in lung function among patients with TB is more likely if patients are < 40 years of age and do not have chronic sequelae.36 Future sarcoidosis clinical investigations should include patients within 1 year of their diagnosis, longer follow-up period assessment for potential steroid-sparing effect, and CT or PET scans. Several studies have shown that increased activity according to a PET scan is a useful predictor of treatment-responsive pulmonary sarcoidosis.37,38 PET scanning was not included in the current study because the information at time of study implementation was incomplete, and the cost of this as an exploratory analysis was prohibitive.
Conclusions
In a cohort of patients with progressive pulmonary sarcoidosis, the CLEAR therapy did not result in significant improvement in percent predicted FVC but, instead, was associated with significant declines in ESAT-6-specific immune responses.
Supplementary Data
e-Online Data
Acknowledgments
Author contributions: W. P. D. had full access to all the data following study completion and assumes full responsibility for the integrity of the data and the accuracy of the data analysis. W. P. D., D. A. C., R. P. B., and G.R.B. were responsible for conception and design; K. A., D. A. C., R. P. B., M. A. J., E. D. C., E. J., and A. G. performed experiments; T. D., G. D. A., G. R. B., and W. P. D. contributed to analysis and interpretation; and W. P. D, D. A. C., R. P. B., M. A. J., E. D. C., E. J., T. D., K. A., A. G., A. K., A.S., and G. R. B. drafted the manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. P. B. received personal fees from Actelion and from Mallinckrodt during the conduct of the study. None declared (W. P. D., D. A. C., M. A. J., E. D. C., E. J., G. D. A., T. D., K. A., A. G., A. K., A. S., G. R. B.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors are grateful for the support of the patients with sarcoidosis and nursing personnel for this investigation.
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
The contents of this article are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
FUNDING/SUPPORT: The publication was supported in part by CTSA award UL1 TR002243 from the 10.13039/100006108 National Center for Advancing Translational Sciences (G. R. B.); R01 HL117074 (W. P. D.); 10.13039/100004319 Pfizer Global Medical Grant Program 53232269; and the Pierce Foundation. | AZITHROMYCIN ANHYDROUS, ETHAMBUTOL HYDROCHLORIDE, LEVOFLOXACIN, RIFABUTIN | DrugsGivenReaction | CC BY-NC-ND | 33387486 | 18,762,907 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'. | Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis.
A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.
The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.
In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.
The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).
Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.
Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1,2 Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3,4
Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5, 6, 7 In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7, 8, 9 Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8 as well as following administration of antimycobacterial therapy to patients with this disease.10 The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10,11 Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11 A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12 We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease.
Patients and Methods
Trial Design and Objectives
This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses.
Protocol Development and Oversight
The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13 This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen.
Interventions
Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269).
Population Eligibility and Randomization
Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1 Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least 5% on serial measurements over 24 months; (2) radiographic progression in chest imaging on side-by-side comparison; or (3) decline in dyspnea score, as measured by using the Transition Dyspnea Index. Prior to randomization, participants were assessed for peripheral immune responses to ESAT-6 or evidence of peripheral anergy as defined by absence of responses to phytohemagglutinin. If either of those conditions were present, the subject was enrolled. Finally, participants were required to have evidence of parenchymal or nodal disease on chest radiograph. Site-specific pulmonologists who were unaffiliated with the CLEAR trial read all site-specific lung function tests.
Sample size was calculated for the primary end point: change from baseline of FVC percent predicted. Using data from participants with chronic pulmonary sarcoidosis treated with infliximab,14 we obtained the SD of 7.7 for the primary end point. A sample size of 51 completed participants per arm was needed to have 90% power to detect a 5% difference in change of FVC percent predicted from baseline.
The major exclusion criteria were as follows:(1) Inability to obtain consent.
(2) Age < 18 years.
(3) Female participants of childbearing potential not willing to use one of the following methods of birth control for the duration of the study and 90 days following study completion: condoms, sponge, foams, jellies, diaphragm, nonhormonal intrauterine device, a vasectomized sole partner, or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test result at screening visit was required if the female subject was of childbearing potential.
(4) FVC predicted value < 45%.
(5) End-stage fibrotic pulmonary disease.
(6) Significant underlying liver disease.
(7) Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
(8) Allergy or intolerance to albuterol.
(9) Poor venous access for obtaining blood samples.
(10) History of active TB, close contact with a person with active TB within the 6 months prior to the screening visit, or a positive purified protein derivative skin test result.
(11) Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation (eg, respiratory, cardiac, neurologic, musculoskeletal, or seizure disorders).
(12) Use of an investigational drug within 30 days prior to screening or within five half-lives of the agent, whichever is longer.
(13) Currently receiving > 40 mg of prednisone.
(14) Alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal.
(15) Leukopenia, as defined by a WBC count < 3.0 cells/mm3 or absolute neutrophil count < 1,000/μL.
(16) Breastfeeding.
(17) Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis.
(18) If the patient is on immunomodulators, they must be on a regimen for 3 months or longer and on a stable dose for > 4 weeks.
(19) Family or personal history of long QT interval.
(20) Most recent nuclear medicine scan or echocardiogram (if performed) showing cardiac ejection fraction < 35%.
(21) Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotic, antiretroviral, or antifungal agents within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis.
(22) Any significant finding in the patient’s medical history or physical or psychiatric examination prior to or following randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol.
(23) Taking medications that, in the opinion of the investigator, would affect patient safety when taken with the antibiotics of the CLEAR regimen.
(24) History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit.
Patients were assigned to receive the CLEAR or placebo regimen by using a block randomization stratified according to site and use of prednisone ≥ 10 mg or not. Randomization lists were generated and distributed to site pharmacies by a statistician at Vanderbilt University Medical Center not associated with the study.
Measurement of Treatment Completion
Patients were requested to bring all remaining doses of every trial drug to each visit for pill counts. Treatment completion for the per-protocol analysis was defined as administration of at least 90% of the doses within 16 weeks.
Measurement of Safety During Treatment
At each follow-up visit, participants were questioned and examined for adverse events. Suspected adverse events were investigated, managed, and reported according to a standardized protocol. Information about suspected adverse events was reviewed and graded by the site-specific principal investigator and clinical coordinator. The severity of adverse events was judged according to the Common Toxicity Criteria for Adverse Events version 4.0. The events were categorized as follows: an adverse event that was not related to a trial drug; an adverse event of grade 1 or 2 that was related to a trial drug (not serious); an adverse event of grade 3 or 4 that was related to a trial drug (generally considered to lead to trial drug discontinuation if related to a trial drug); or a grade 5 event (death) that was related to a trial drug. Each adverse event resulting in organ impairment, hospitalization, or death was defined as a serious adverse event (SAE). An SAE was reported and reviewed by the institutional review board, as well as the four-member Data Safety Monitoring Board. The board provided oversight regarding safety for continuation of the study.
Oversight
This trial was approved by the Vanderbilt University Human Research Protection Program and by the institutional review board at each participating site. All the authors vouch for the accuracy and completeness of the data and analyses presented and for the compliance of the trial to the protocol.
Statistical Analysis
This randomized Phase II clinical trial was conducted to determine if CLEAR elicits a statistically significant (two-sided value P < .05) improvement in respiratory performance, the 6MWD, SGRQ, and immune responses against ESAT-6. Ninety-seven patients were randomized to treatment from May 5, 2014, to December 13, 2018, of whom 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were cleaned and locked for final analysis on April 18, 2019. The primary end point was baseline to 16-week change in preinhaler FVC as percent predicted. We defined the 16-week postrandomization FVC percent predicted value measurement as the value closest to 16 weeks from randomization within a window of 12 to 20 weeks from randomization.
The primary comparison between the CLEAR and placebo arms was conducted on an intention-to-treat (as randomized) basis among patients with both baseline and 16-week outcomes (N = 97). Unless otherwise stated, mean, SE, and comparative P values were estimates with multiple imputation using predictive mean matching with aregImpute, as previously described.15,16 The multiple imputation data sets were summarized according to Rubin’s rules.17 Unless otherwise noted, figures represent the mean change score ± the SE computed by using Rubin’s rules for imputed data. Change scores for secondary end points were compared by using the linear model formulation of the two-sample test between groups over 100 imputed data sets. The paired Student t test for multiply imputed data was used to compare baseline and 16-week change scores within each treatment group at 8 and 16 weeks. All analyses were repeated for a per-protocol population of patients (n = 72). Analysis of ESAT-6 and adverse events was not based on imputed data. The ESAT-6 analysis was the only within-group comparison and was conducted by using a Student paired t test, comparing baseline with 16-week values within their randomization cohort. The number of subjects experiencing an SAE and separately an adverse event (adverse events not including SAEs) was compared between treatment arms by using the paired or unpaired Student t test.
Results
Trial Participants
We screened 446 potential patients from May 2014 through December 2018, of whom 97 were enrolled and randomized to treatment (Fig 1). The most common reasons for exclusion from study participation were as follows: (1) significant comorbid conditions; (2) a history of a drug interaction between one of the CLEAR antibiotics with a medication that the patient was currently receiving; (3) patient declined to participate; (4) pulmonary hypertension treatment; (5) concerns for noncompliance with study visits; and (6) Scadding stage IV fibrosis detected on a chest radiograph.Figure 1 Consort Diagram of Phase IIB investigation of the efficacy of antimycobacterial therapy against progressive pulmonary sarcoidosis. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; LTBI = latent TB infection.
The demographic and clinical characteristics of all study participants according to their randomization group are shown in Table 1. Of the 97 enrolled subjects, baseline characteristics were well balanced across treatment arms. Approximately one-half of the population (n = 50 [52%]) was female, and the majority were White (n = 68 [70%]), with approximately one-third African American (n = 28 [29%]). A possible balance exception was sex (59% women in the placebo group and 44% women in the CLEAR group). Although not a planned analysis, analysis of covariance of sex (P = .996) with treatment group (P = .903) on nonimputed data, as with their interaction (P = .678), suggests no confounding by sex.Table 1 Patient Demographic Characteristics According to Therapeutic Regimen
Characteristic CLEAR Placebo Combined
(n = 49) (n = 48) (N = 97)
Age, mean ± SD, y 54.5 ± 9.8 54.5 ± 9.8 54.5 ± 10
Sex
Male 20 (41%) 27 (56%) 47 (48%)
Female 29 (59%) 21 (44%) 50 (52%)
Race
African American 15 (31%) 13 (27%) 28 (29%)
White 34 (69%) 34 (71%) 68 (70%)
Hawaiian or Pacific Islander 0 (0) 1 (2%) 1 (1%)
Ethnicity
Non-Hispanic/nor Latino 48 (98%) 46 (96%) 94 (97%)
Hispanic/Latino 1 (2%) 2 (4%) 3 (3%)
Baseline end points
Preinhaler FVC % 77.3 ± 13.7 75.5 ± 14.5 75.4 ± 14.1
6-min walk test, ma 416.2 ± 140.7 416.4 ± 105.2 416.3 ± 123.5
SGRQ activityb 57.7 ± 23.2 55.5 ± 24.5 56.6 ± 23.8
SGRQ impactb 34.8 ± 22.2 32.9 ± 19.8 33.8 ± 20.9
SGRQ symptomsb 53.9 ± 23.8 50.5 ± 19.3 52.2 ± 21.7
SGRQ totalb 44.9 ± 21.1 42.7 ± 18.7 43.8 ± 19.9
Immunosuppression
Patients on prednisone (mean dosage) 23 (47%) (10 mg) 19 (40%) (10 mg) 42 (43%) (10 mg)
Patients on a DMA 19 (39%) 17 (35%) 36 (37%)
Patients on a biologic agent 1 (2%) 1 (2%) 2 (4%)
Patients on prednisone plus a DMA or biologic agent 10 (20%) 6 (13%) 16 (16%)
Patients on any combination of prednisone, DMA, or biologic agent 11 (22%) 8 (17%) 19 (20%)
ESAT-6 positivity
Yes 39 (80%) 36 (75%) 75 (77%)
Equivocal 10 (20%) 12 (25%) 25 (23%)
CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; DMA = disease-modifying agent; ESAT-6 = early secreted antigenic target of 6 kDa.
a N = 48 for CLEAR and placebo groups.
b N = 48 and N = 47, for CLEAR and placebo groups, respectively.
The clinical data were analyzed via intention-to-treat and per protocol. No subjects were excluded from the intention-to-treat analysis. In the per-protocol analysis, 25 (12 in the active arm and 13 in the placebo arm) of the 97 patients were excluded because of failure to take > 4 weeks of the prescribed regimen (CLEAR, n = 8; placebo, n = 4), alteration in clinical immunosuppressive regimen while on study drugs (CLEAR, n = 1; placebo, n = 3), initiation of non-study antibiotics during study participation (CLEAR, n = 1; placebo, n = 3), and found to be receiving antibiotics with antimycobacterial therapy, such as trimethoprim-sulfamethoxazole, at the time of enrollment (CLEAR, n = 2; placebo, n = 3). The remaining 72 subjects were included in the per-protocol analysis.
Efficacy
In the intention-to-treat analysis, there were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between the CLEAR and placebo groups (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64) (Fig 2A, Table 2). Eight-eight patients experienced follow-up during the 12- to 20-week postrandomization window. Median (interquartile range) and mean ± SD of time to the date of FVC percent measurement was 17 (16.1-18) weeks and 17.5 ± 1.9 weeks, respectively. Time to primary end point measurement was equivalent between treatment groups, with a median (interquartile range) of 17 (16.2-18) weeks for placebo and 17.2 (16.2-18.0) weeks for CLEAR II patients. Mean ± SD values were 17.5 ± 1.9 and 17.4 ± 1.8. Evaluation of other physiological parameters, such as 6MWD (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = .91) revealed no statistically significant differences (Fig 2B). A negative change in the SGRQ score reflects an improvement in quality of life. The SRGQ did reveal statistically and clinically significant differences in favor of the placebo group (placebo, –7.97; CLEAR II, –1.52; P = .028, minimal clinically important difference = 4.0).Figure 2 A-B, Graphic depiction of intention-to-treat assessment of physiological parameters such as FVC and 6-min walk distance in 97 subjects with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, There were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between 49 CLEAR and 48 placebo subjects (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64). B, Evaluation of 6-min walk distance (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = 0.91) revealed no statistically significant difference. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Table 2 Physiological and Qualitative End Point Analyses
Variable Placebo CLEAR P Value
Intent-to-treat population
Preinhaler FVC % 0.02 ± 1.47 –1.06 ± 1.85 .640
6-min walk distance 12.40 ± 12.35 9.78 ± 19.31 .908
SGRQ activity –7.15 ± 3.28 –0.96 ± 2.87 .162
SGRQ impact –7.45 ± 2.64 –0.61 ± 2.78 .057
SGRQ symptoms –10.15 ± 3.45 –5.62 ± 3.22 .331
SGRQ total –7.97 ± 2.01 –1.52 ± 2.17 .028
Per-protocol group
Preinhaler FVC % 0.42 ± 1.48 –0.74 ± 1.75 .616
6-min walk distance 6.27 ± 11.99 36.35 ± 22.32 .242
SGRQ activity –4.25 ± 2.39 –1.45 ± 2.91 .458
SGRQ impact –7.97 ± 2.51 –1,10 ± 2.62 .061
SGRQ symptoms –9.78 ± 3.60 –8.07 ± 3.39 .730
SGRQ total –6.97 ± 2.13 –2.32 ± 2.32 .141
Imputed mean ± SE of baseline to 16-week differences in measurements. P values are from imputation-based two-sample Student t test. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; SGRQ = St. George’s Respiratory Questionnaire.
In the per-protocol analysis, 72 subjects were analyzed following removal of 25 patients prior to data analysis due to factors outlined in the protocol. Comparison of baseline vs week 16 end points of the remaining 72 patients revealed that there were no statistically differences in the primary end point (the change from baseline in percent predicted FVC) between 37 CLEAR-treated patients compared with 35 patients receiving placebo (CLEAR –0.74% vs placebo 0.42%; P = .62) (Fig 3A, Table 2). Evaluation of other physiological and qualitative end points revealed no significant differences; for example, there were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = .242) (Fig 3B). The SGRQ also revealed no significant differences in the total score between the groups (placebo, –6.9; CLEAR, –2.3; imputed two-sample Student t test, P = .14). CLEAR-treated patients had less improvement in activity, impact, and symptoms compared with patients receiving placebo.Figure 3 A-B, Graphic depiction of per-protocol assessment of physiologic parameters, such as FVC and placebo in 97 patients with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, Comparison of baseline vs week 16 end points of 72 subjects revealed that there were no statistically differences in the primary end point (change from baseline in percent predicted FVC) between 37 CLEAR subjects compared with 35 placebo subjects (CLEAR –0.74% vs placebo 0.42%; imputed two-sample Student t test, P = .62). B, Evaluation of 6-min walk distance revealed no significant difference among patients randomized to the CLEAR or the placebo regimen (36.4 m vs 6.3 m; imputed two-sample Student t test, P = .242). CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Although there was no significant baseline difference in ESAT-6-specific spot-forming units between the two groups (unpaired Student t test, P = .48) (Fig 4A), there was a significant difference in the spot-forming units following 16 weeks of therapy. There was no significant change in 38 subjects randomized to receive placebo (paired Student t test, P = .26) (Fig 4B); however, a significant decline in the ESAT-6 spot-forming units among the 31 patients randomized to the CLEAR regimen (paired Student t test, P = .0003) (Fig 4C). Only subjects for whom baseline and 16-week values were available were included in this analysis.Figure 4 Comparison of ESAT-6 immune responses at baseline (n = 69 subjects) (A), as well as baseline to 16 weeks among patients with sarcoidosis randomized to either the placebo (n = 38 subjects) (B) or CLEAR (n = 31 subjects) (C) regimen. ESAT-6 = early secreted antigenic target of 6 kDa; NS = not significant; PBMC = peripheral blood mononuclear cells; SFU = spot-forming units.
Safety
At each follow-up visit, participants were evaluated for adverse events. A total of 75 adverse events were noted in 39 subjects (e-Table 1). Any adverse event resulting in organ impairment, hospitalization, or death was defined as an SAE. The number of SAEs was similar for CLEAR (n = 4) and placebo (n = 3) (P = .72) (Table 3). Three of the four SAEs in the CLEAR cohort were believed to be related to study drugs; none was believed to be related in the placebo cohort. There were no deaths in this trial.Table 3 SAEs Throughout the Study
SAE Number Event Group Institution Date Anticipated Caused by Therapy
1 Leukopenia Active Cincinnati 08/14/2016 Yes Probable
2 Pneumonia Active Cincinnati 11/06/2014 Yes Probable
3 Neurosarcoidosis Active Vanderbilt 12/28/2016 No Not related
4 Hypotension Active AMC 01/29/2018 Yes Probable
5 Sepsis from abscess Placebo Cleveland 07/18/2017 No Not related
6 Postoperative infection Placebo Cleveland 11/14/2014 No Unlikely
7 Pneumonia Placebo Cleveland 06/04/2018 No Not related
AMC = Albany Medical College; SAE = severe adverse event.
Discussion
In this randomized, double-blind, placebo-controlled trial of CLEAR therapy, we observed no benefit from the study intervention on pulmonary function, for both the intention-to-treat and per-protocol analyses. Most secondary end points, such as 6MWD and SGRQ, showed no significant improvement from CLEAR, and SGRQ was worse at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated subjects, but no change was observed among those randomized to receive placebo (Figs 3, 4).
Although viable mycobacteria have been proposed to be causative agents for sarcoidosis, the current study provides no evidence to support that hypothesis. The current results are discordant from a randomized trial in which CLEAR therapy was beneficial for cutaneous sarcoidosis, and they also diverge from an uncontrolled report of CLEAR therapy.10,11 One explanation for the failure of CLEAR therapy is that the underlying hypothesis regarding the cause of sarcoidosis is incorrect. This explanation accords with the failure of prior studies to culture mycobacteria from sarcoidosis tissues.18,19
Other explanations for the failure of CLEAR therapy should also be considered. The inclusion criteria were designed to enroll a population with actively progressing sarcoidosis, but the precision of the longitudinal data supporting progression, and the long time window for demonstrating progression, are both problematic and may have biased the study population to include patients with relatively stable, adequately controlled disease.20 Progression in the placebo group on stable therapy would not be expected in a 16-week time frame. Active withdrawal of anti-sarcoidosis medications may be necessary to uncover relative treatment benefits if the effect size is modest, but this study required stable dosing throughout the treatment period. It is also possible that the treatment duration was too short to discern efficacy of therapy; medications such as methotrexate require up to 6 months to effect benefit in pulmonary sarcoidosis.21 Antibiotic therapy may not result in improved FVC; one study noted that these patients may continue to experience an FVC decline, but it occurs at a significantly lower rate than patients who were not successfully treated.22 Finally, FVC may be an insensitive marker of treatment effect; it has previously been shown to correlate poorly with symptoms and with chest imaging.23,24 However, the absence of any observable clinical benefits argues that the end point chosen here is likely not the cause of the negative result.
Immune responses against mycobacterial antigens, such as ESAT-6 and katG, are present in patients with active sarcoidosis disease.8,25,26 Independent investigators found that, using the ELISpot assay, antimycobacterial responses disappear with clinical resolution of sarcoidosis.8 Immune responses against ESAT-6 have also been detected with active or latent TB, as well as other nontuberculous mycobacteria infections27, 28, 29; these responses decline with effective antimycobacterial therapy.30, 31, 32 A significant decline in the ESAT-6 immune responses among subjects randomized to receive CLEAR (but not placebo) is provocative and of uncertain significance. It is unlikely that the decrease in ESAT-6 response in the CLEAR group is due to an immunosuppressant effect of one or more antibiotics in the treatment regimen because we previously reported improved immune function, including enhanced T-cell proliferative capacity and increased IL-2 and interferon-γ secretion, as well as augmented JAK-STAT signaling from sarcoidosis CD4+ T cells, following completion of the CLEAR regimen.11 The improvement in cellular immunity with CLEAR treatment of sarcoidosis could result in the augmented capacity to remove pathogenic microbial antigens such as ESAT-6. In addition, because the removal of microbial antigens such as ESAT-6 during treatment of mycobacterial infection reduces expression of profibrotic cytokines such as IL-17A, this mechanism may also mitigate the development of lung fibrosis during the treatment of sarcoidosis. The discrepancy between measurable declines in a virulence factor associated with active mycobacterial replication (ESAT-6) and the negative results of the current study remain unexplained.
It may be that mycobacterial antigens are important initial triggers of some cases of sarcoidosis, as suggested by persistence of mycobacterial antigens in sarcoidosis tissues,7 but viable infection is not integral to the perpetuation or progression of the disease. Also, because the study design did not obtain any samples to exclude the presence of infection in the subjects, it remains possible that the effects of CLEAR resulted in changes in the microbiome, which could then affect immune responses by changing the presence of microbial antigens. Future investigation regarding the impact of the CLEAR regimen on preventing further lung deterioration is warranted.
The current study did have some limitations. The number of subjects was relatively small. Twenty-five of the 97 patients were excluded from the per-protocol analysis, representing approximately 26% of the enrolled subjects. Twelve of those subjects (CLEAR, n = 8; placebo, n = 4) were excluded due to taking < 4 weeks of study medications, making it more difficult to assess the impact of 16 weeks of CLEAR therapy on the primary and secondary end points. Due to the pill burden and toxicities associated with a four-drug regimen, difficulty adhering to antimycobacterial therapy is well documented.33, 34, 35 Toxicities, such as myalgias and arthralgias from azithromycin and levofloxacin, as well as fatigue from rifabutin, may have affected the SGRQ score, masking our ability to clearly delineate an anti-sarcoidosis effect. Higher SGRQ scores were noted among CLEAR-treated patients experiencing these toxicities. Another limitation is the failure to include patients with disease for < 1 year. We did not include patients within 1 year of diagnosis because it was believed that differentiation of drug efficacy from spontaneous resolution would be too difficult. However, improvement in lung function among patients with TB is more likely if patients are < 40 years of age and do not have chronic sequelae.36 Future sarcoidosis clinical investigations should include patients within 1 year of their diagnosis, longer follow-up period assessment for potential steroid-sparing effect, and CT or PET scans. Several studies have shown that increased activity according to a PET scan is a useful predictor of treatment-responsive pulmonary sarcoidosis.37,38 PET scanning was not included in the current study because the information at time of study implementation was incomplete, and the cost of this as an exploratory analysis was prohibitive.
Conclusions
In a cohort of patients with progressive pulmonary sarcoidosis, the CLEAR therapy did not result in significant improvement in percent predicted FVC but, instead, was associated with significant declines in ESAT-6-specific immune responses.
Supplementary Data
e-Online Data
Acknowledgments
Author contributions: W. P. D. had full access to all the data following study completion and assumes full responsibility for the integrity of the data and the accuracy of the data analysis. W. P. D., D. A. C., R. P. B., and G.R.B. were responsible for conception and design; K. A., D. A. C., R. P. B., M. A. J., E. D. C., E. J., and A. G. performed experiments; T. D., G. D. A., G. R. B., and W. P. D. contributed to analysis and interpretation; and W. P. D, D. A. C., R. P. B., M. A. J., E. D. C., E. J., T. D., K. A., A. G., A. K., A.S., and G. R. B. drafted the manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. P. B. received personal fees from Actelion and from Mallinckrodt during the conduct of the study. None declared (W. P. D., D. A. C., M. A. J., E. D. C., E. J., G. D. A., T. D., K. A., A. G., A. K., A. S., G. R. B.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors are grateful for the support of the patients with sarcoidosis and nursing personnel for this investigation.
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
The contents of this article are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
FUNDING/SUPPORT: The publication was supported in part by CTSA award UL1 TR002243 from the 10.13039/100006108 National Center for Advancing Translational Sciences (G. R. B.); R01 HL117074 (W. P. D.); 10.13039/100004319 Pfizer Global Medical Grant Program 53232269; and the Pierce Foundation. | AZITHROMYCIN ANHYDROUS, ETHAMBUTOL HYDROCHLORIDE, LEVOFLOXACIN, RIFABUTIN | DrugsGivenReaction | CC BY-NC-ND | 33387486 | 18,762,907 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis.
A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.
The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.
In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.
The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).
Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.
Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1,2 Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3,4
Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5, 6, 7 In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7, 8, 9 Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8 as well as following administration of antimycobacterial therapy to patients with this disease.10 The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10,11 Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11 A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12 We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease.
Patients and Methods
Trial Design and Objectives
This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses.
Protocol Development and Oversight
The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13 This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen.
Interventions
Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269).
Population Eligibility and Randomization
Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1 Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least 5% on serial measurements over 24 months; (2) radiographic progression in chest imaging on side-by-side comparison; or (3) decline in dyspnea score, as measured by using the Transition Dyspnea Index. Prior to randomization, participants were assessed for peripheral immune responses to ESAT-6 or evidence of peripheral anergy as defined by absence of responses to phytohemagglutinin. If either of those conditions were present, the subject was enrolled. Finally, participants were required to have evidence of parenchymal or nodal disease on chest radiograph. Site-specific pulmonologists who were unaffiliated with the CLEAR trial read all site-specific lung function tests.
Sample size was calculated for the primary end point: change from baseline of FVC percent predicted. Using data from participants with chronic pulmonary sarcoidosis treated with infliximab,14 we obtained the SD of 7.7 for the primary end point. A sample size of 51 completed participants per arm was needed to have 90% power to detect a 5% difference in change of FVC percent predicted from baseline.
The major exclusion criteria were as follows:(1) Inability to obtain consent.
(2) Age < 18 years.
(3) Female participants of childbearing potential not willing to use one of the following methods of birth control for the duration of the study and 90 days following study completion: condoms, sponge, foams, jellies, diaphragm, nonhormonal intrauterine device, a vasectomized sole partner, or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test result at screening visit was required if the female subject was of childbearing potential.
(4) FVC predicted value < 45%.
(5) End-stage fibrotic pulmonary disease.
(6) Significant underlying liver disease.
(7) Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
(8) Allergy or intolerance to albuterol.
(9) Poor venous access for obtaining blood samples.
(10) History of active TB, close contact with a person with active TB within the 6 months prior to the screening visit, or a positive purified protein derivative skin test result.
(11) Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation (eg, respiratory, cardiac, neurologic, musculoskeletal, or seizure disorders).
(12) Use of an investigational drug within 30 days prior to screening or within five half-lives of the agent, whichever is longer.
(13) Currently receiving > 40 mg of prednisone.
(14) Alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal.
(15) Leukopenia, as defined by a WBC count < 3.0 cells/mm3 or absolute neutrophil count < 1,000/μL.
(16) Breastfeeding.
(17) Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis.
(18) If the patient is on immunomodulators, they must be on a regimen for 3 months or longer and on a stable dose for > 4 weeks.
(19) Family or personal history of long QT interval.
(20) Most recent nuclear medicine scan or echocardiogram (if performed) showing cardiac ejection fraction < 35%.
(21) Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotic, antiretroviral, or antifungal agents within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis.
(22) Any significant finding in the patient’s medical history or physical or psychiatric examination prior to or following randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol.
(23) Taking medications that, in the opinion of the investigator, would affect patient safety when taken with the antibiotics of the CLEAR regimen.
(24) History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit.
Patients were assigned to receive the CLEAR or placebo regimen by using a block randomization stratified according to site and use of prednisone ≥ 10 mg or not. Randomization lists were generated and distributed to site pharmacies by a statistician at Vanderbilt University Medical Center not associated with the study.
Measurement of Treatment Completion
Patients were requested to bring all remaining doses of every trial drug to each visit for pill counts. Treatment completion for the per-protocol analysis was defined as administration of at least 90% of the doses within 16 weeks.
Measurement of Safety During Treatment
At each follow-up visit, participants were questioned and examined for adverse events. Suspected adverse events were investigated, managed, and reported according to a standardized protocol. Information about suspected adverse events was reviewed and graded by the site-specific principal investigator and clinical coordinator. The severity of adverse events was judged according to the Common Toxicity Criteria for Adverse Events version 4.0. The events were categorized as follows: an adverse event that was not related to a trial drug; an adverse event of grade 1 or 2 that was related to a trial drug (not serious); an adverse event of grade 3 or 4 that was related to a trial drug (generally considered to lead to trial drug discontinuation if related to a trial drug); or a grade 5 event (death) that was related to a trial drug. Each adverse event resulting in organ impairment, hospitalization, or death was defined as a serious adverse event (SAE). An SAE was reported and reviewed by the institutional review board, as well as the four-member Data Safety Monitoring Board. The board provided oversight regarding safety for continuation of the study.
Oversight
This trial was approved by the Vanderbilt University Human Research Protection Program and by the institutional review board at each participating site. All the authors vouch for the accuracy and completeness of the data and analyses presented and for the compliance of the trial to the protocol.
Statistical Analysis
This randomized Phase II clinical trial was conducted to determine if CLEAR elicits a statistically significant (two-sided value P < .05) improvement in respiratory performance, the 6MWD, SGRQ, and immune responses against ESAT-6. Ninety-seven patients were randomized to treatment from May 5, 2014, to December 13, 2018, of whom 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were cleaned and locked for final analysis on April 18, 2019. The primary end point was baseline to 16-week change in preinhaler FVC as percent predicted. We defined the 16-week postrandomization FVC percent predicted value measurement as the value closest to 16 weeks from randomization within a window of 12 to 20 weeks from randomization.
The primary comparison between the CLEAR and placebo arms was conducted on an intention-to-treat (as randomized) basis among patients with both baseline and 16-week outcomes (N = 97). Unless otherwise stated, mean, SE, and comparative P values were estimates with multiple imputation using predictive mean matching with aregImpute, as previously described.15,16 The multiple imputation data sets were summarized according to Rubin’s rules.17 Unless otherwise noted, figures represent the mean change score ± the SE computed by using Rubin’s rules for imputed data. Change scores for secondary end points were compared by using the linear model formulation of the two-sample test between groups over 100 imputed data sets. The paired Student t test for multiply imputed data was used to compare baseline and 16-week change scores within each treatment group at 8 and 16 weeks. All analyses were repeated for a per-protocol population of patients (n = 72). Analysis of ESAT-6 and adverse events was not based on imputed data. The ESAT-6 analysis was the only within-group comparison and was conducted by using a Student paired t test, comparing baseline with 16-week values within their randomization cohort. The number of subjects experiencing an SAE and separately an adverse event (adverse events not including SAEs) was compared between treatment arms by using the paired or unpaired Student t test.
Results
Trial Participants
We screened 446 potential patients from May 2014 through December 2018, of whom 97 were enrolled and randomized to treatment (Fig 1). The most common reasons for exclusion from study participation were as follows: (1) significant comorbid conditions; (2) a history of a drug interaction between one of the CLEAR antibiotics with a medication that the patient was currently receiving; (3) patient declined to participate; (4) pulmonary hypertension treatment; (5) concerns for noncompliance with study visits; and (6) Scadding stage IV fibrosis detected on a chest radiograph.Figure 1 Consort Diagram of Phase IIB investigation of the efficacy of antimycobacterial therapy against progressive pulmonary sarcoidosis. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; LTBI = latent TB infection.
The demographic and clinical characteristics of all study participants according to their randomization group are shown in Table 1. Of the 97 enrolled subjects, baseline characteristics were well balanced across treatment arms. Approximately one-half of the population (n = 50 [52%]) was female, and the majority were White (n = 68 [70%]), with approximately one-third African American (n = 28 [29%]). A possible balance exception was sex (59% women in the placebo group and 44% women in the CLEAR group). Although not a planned analysis, analysis of covariance of sex (P = .996) with treatment group (P = .903) on nonimputed data, as with their interaction (P = .678), suggests no confounding by sex.Table 1 Patient Demographic Characteristics According to Therapeutic Regimen
Characteristic CLEAR Placebo Combined
(n = 49) (n = 48) (N = 97)
Age, mean ± SD, y 54.5 ± 9.8 54.5 ± 9.8 54.5 ± 10
Sex
Male 20 (41%) 27 (56%) 47 (48%)
Female 29 (59%) 21 (44%) 50 (52%)
Race
African American 15 (31%) 13 (27%) 28 (29%)
White 34 (69%) 34 (71%) 68 (70%)
Hawaiian or Pacific Islander 0 (0) 1 (2%) 1 (1%)
Ethnicity
Non-Hispanic/nor Latino 48 (98%) 46 (96%) 94 (97%)
Hispanic/Latino 1 (2%) 2 (4%) 3 (3%)
Baseline end points
Preinhaler FVC % 77.3 ± 13.7 75.5 ± 14.5 75.4 ± 14.1
6-min walk test, ma 416.2 ± 140.7 416.4 ± 105.2 416.3 ± 123.5
SGRQ activityb 57.7 ± 23.2 55.5 ± 24.5 56.6 ± 23.8
SGRQ impactb 34.8 ± 22.2 32.9 ± 19.8 33.8 ± 20.9
SGRQ symptomsb 53.9 ± 23.8 50.5 ± 19.3 52.2 ± 21.7
SGRQ totalb 44.9 ± 21.1 42.7 ± 18.7 43.8 ± 19.9
Immunosuppression
Patients on prednisone (mean dosage) 23 (47%) (10 mg) 19 (40%) (10 mg) 42 (43%) (10 mg)
Patients on a DMA 19 (39%) 17 (35%) 36 (37%)
Patients on a biologic agent 1 (2%) 1 (2%) 2 (4%)
Patients on prednisone plus a DMA or biologic agent 10 (20%) 6 (13%) 16 (16%)
Patients on any combination of prednisone, DMA, or biologic agent 11 (22%) 8 (17%) 19 (20%)
ESAT-6 positivity
Yes 39 (80%) 36 (75%) 75 (77%)
Equivocal 10 (20%) 12 (25%) 25 (23%)
CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; DMA = disease-modifying agent; ESAT-6 = early secreted antigenic target of 6 kDa.
a N = 48 for CLEAR and placebo groups.
b N = 48 and N = 47, for CLEAR and placebo groups, respectively.
The clinical data were analyzed via intention-to-treat and per protocol. No subjects were excluded from the intention-to-treat analysis. In the per-protocol analysis, 25 (12 in the active arm and 13 in the placebo arm) of the 97 patients were excluded because of failure to take > 4 weeks of the prescribed regimen (CLEAR, n = 8; placebo, n = 4), alteration in clinical immunosuppressive regimen while on study drugs (CLEAR, n = 1; placebo, n = 3), initiation of non-study antibiotics during study participation (CLEAR, n = 1; placebo, n = 3), and found to be receiving antibiotics with antimycobacterial therapy, such as trimethoprim-sulfamethoxazole, at the time of enrollment (CLEAR, n = 2; placebo, n = 3). The remaining 72 subjects were included in the per-protocol analysis.
Efficacy
In the intention-to-treat analysis, there were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between the CLEAR and placebo groups (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64) (Fig 2A, Table 2). Eight-eight patients experienced follow-up during the 12- to 20-week postrandomization window. Median (interquartile range) and mean ± SD of time to the date of FVC percent measurement was 17 (16.1-18) weeks and 17.5 ± 1.9 weeks, respectively. Time to primary end point measurement was equivalent between treatment groups, with a median (interquartile range) of 17 (16.2-18) weeks for placebo and 17.2 (16.2-18.0) weeks for CLEAR II patients. Mean ± SD values were 17.5 ± 1.9 and 17.4 ± 1.8. Evaluation of other physiological parameters, such as 6MWD (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = .91) revealed no statistically significant differences (Fig 2B). A negative change in the SGRQ score reflects an improvement in quality of life. The SRGQ did reveal statistically and clinically significant differences in favor of the placebo group (placebo, –7.97; CLEAR II, –1.52; P = .028, minimal clinically important difference = 4.0).Figure 2 A-B, Graphic depiction of intention-to-treat assessment of physiological parameters such as FVC and 6-min walk distance in 97 subjects with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, There were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between 49 CLEAR and 48 placebo subjects (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64). B, Evaluation of 6-min walk distance (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = 0.91) revealed no statistically significant difference. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Table 2 Physiological and Qualitative End Point Analyses
Variable Placebo CLEAR P Value
Intent-to-treat population
Preinhaler FVC % 0.02 ± 1.47 –1.06 ± 1.85 .640
6-min walk distance 12.40 ± 12.35 9.78 ± 19.31 .908
SGRQ activity –7.15 ± 3.28 –0.96 ± 2.87 .162
SGRQ impact –7.45 ± 2.64 –0.61 ± 2.78 .057
SGRQ symptoms –10.15 ± 3.45 –5.62 ± 3.22 .331
SGRQ total –7.97 ± 2.01 –1.52 ± 2.17 .028
Per-protocol group
Preinhaler FVC % 0.42 ± 1.48 –0.74 ± 1.75 .616
6-min walk distance 6.27 ± 11.99 36.35 ± 22.32 .242
SGRQ activity –4.25 ± 2.39 –1.45 ± 2.91 .458
SGRQ impact –7.97 ± 2.51 –1,10 ± 2.62 .061
SGRQ symptoms –9.78 ± 3.60 –8.07 ± 3.39 .730
SGRQ total –6.97 ± 2.13 –2.32 ± 2.32 .141
Imputed mean ± SE of baseline to 16-week differences in measurements. P values are from imputation-based two-sample Student t test. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; SGRQ = St. George’s Respiratory Questionnaire.
In the per-protocol analysis, 72 subjects were analyzed following removal of 25 patients prior to data analysis due to factors outlined in the protocol. Comparison of baseline vs week 16 end points of the remaining 72 patients revealed that there were no statistically differences in the primary end point (the change from baseline in percent predicted FVC) between 37 CLEAR-treated patients compared with 35 patients receiving placebo (CLEAR –0.74% vs placebo 0.42%; P = .62) (Fig 3A, Table 2). Evaluation of other physiological and qualitative end points revealed no significant differences; for example, there were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = .242) (Fig 3B). The SGRQ also revealed no significant differences in the total score between the groups (placebo, –6.9; CLEAR, –2.3; imputed two-sample Student t test, P = .14). CLEAR-treated patients had less improvement in activity, impact, and symptoms compared with patients receiving placebo.Figure 3 A-B, Graphic depiction of per-protocol assessment of physiologic parameters, such as FVC and placebo in 97 patients with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, Comparison of baseline vs week 16 end points of 72 subjects revealed that there were no statistically differences in the primary end point (change from baseline in percent predicted FVC) between 37 CLEAR subjects compared with 35 placebo subjects (CLEAR –0.74% vs placebo 0.42%; imputed two-sample Student t test, P = .62). B, Evaluation of 6-min walk distance revealed no significant difference among patients randomized to the CLEAR or the placebo regimen (36.4 m vs 6.3 m; imputed two-sample Student t test, P = .242). CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Although there was no significant baseline difference in ESAT-6-specific spot-forming units between the two groups (unpaired Student t test, P = .48) (Fig 4A), there was a significant difference in the spot-forming units following 16 weeks of therapy. There was no significant change in 38 subjects randomized to receive placebo (paired Student t test, P = .26) (Fig 4B); however, a significant decline in the ESAT-6 spot-forming units among the 31 patients randomized to the CLEAR regimen (paired Student t test, P = .0003) (Fig 4C). Only subjects for whom baseline and 16-week values were available were included in this analysis.Figure 4 Comparison of ESAT-6 immune responses at baseline (n = 69 subjects) (A), as well as baseline to 16 weeks among patients with sarcoidosis randomized to either the placebo (n = 38 subjects) (B) or CLEAR (n = 31 subjects) (C) regimen. ESAT-6 = early secreted antigenic target of 6 kDa; NS = not significant; PBMC = peripheral blood mononuclear cells; SFU = spot-forming units.
Safety
At each follow-up visit, participants were evaluated for adverse events. A total of 75 adverse events were noted in 39 subjects (e-Table 1). Any adverse event resulting in organ impairment, hospitalization, or death was defined as an SAE. The number of SAEs was similar for CLEAR (n = 4) and placebo (n = 3) (P = .72) (Table 3). Three of the four SAEs in the CLEAR cohort were believed to be related to study drugs; none was believed to be related in the placebo cohort. There were no deaths in this trial.Table 3 SAEs Throughout the Study
SAE Number Event Group Institution Date Anticipated Caused by Therapy
1 Leukopenia Active Cincinnati 08/14/2016 Yes Probable
2 Pneumonia Active Cincinnati 11/06/2014 Yes Probable
3 Neurosarcoidosis Active Vanderbilt 12/28/2016 No Not related
4 Hypotension Active AMC 01/29/2018 Yes Probable
5 Sepsis from abscess Placebo Cleveland 07/18/2017 No Not related
6 Postoperative infection Placebo Cleveland 11/14/2014 No Unlikely
7 Pneumonia Placebo Cleveland 06/04/2018 No Not related
AMC = Albany Medical College; SAE = severe adverse event.
Discussion
In this randomized, double-blind, placebo-controlled trial of CLEAR therapy, we observed no benefit from the study intervention on pulmonary function, for both the intention-to-treat and per-protocol analyses. Most secondary end points, such as 6MWD and SGRQ, showed no significant improvement from CLEAR, and SGRQ was worse at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated subjects, but no change was observed among those randomized to receive placebo (Figs 3, 4).
Although viable mycobacteria have been proposed to be causative agents for sarcoidosis, the current study provides no evidence to support that hypothesis. The current results are discordant from a randomized trial in which CLEAR therapy was beneficial for cutaneous sarcoidosis, and they also diverge from an uncontrolled report of CLEAR therapy.10,11 One explanation for the failure of CLEAR therapy is that the underlying hypothesis regarding the cause of sarcoidosis is incorrect. This explanation accords with the failure of prior studies to culture mycobacteria from sarcoidosis tissues.18,19
Other explanations for the failure of CLEAR therapy should also be considered. The inclusion criteria were designed to enroll a population with actively progressing sarcoidosis, but the precision of the longitudinal data supporting progression, and the long time window for demonstrating progression, are both problematic and may have biased the study population to include patients with relatively stable, adequately controlled disease.20 Progression in the placebo group on stable therapy would not be expected in a 16-week time frame. Active withdrawal of anti-sarcoidosis medications may be necessary to uncover relative treatment benefits if the effect size is modest, but this study required stable dosing throughout the treatment period. It is also possible that the treatment duration was too short to discern efficacy of therapy; medications such as methotrexate require up to 6 months to effect benefit in pulmonary sarcoidosis.21 Antibiotic therapy may not result in improved FVC; one study noted that these patients may continue to experience an FVC decline, but it occurs at a significantly lower rate than patients who were not successfully treated.22 Finally, FVC may be an insensitive marker of treatment effect; it has previously been shown to correlate poorly with symptoms and with chest imaging.23,24 However, the absence of any observable clinical benefits argues that the end point chosen here is likely not the cause of the negative result.
Immune responses against mycobacterial antigens, such as ESAT-6 and katG, are present in patients with active sarcoidosis disease.8,25,26 Independent investigators found that, using the ELISpot assay, antimycobacterial responses disappear with clinical resolution of sarcoidosis.8 Immune responses against ESAT-6 have also been detected with active or latent TB, as well as other nontuberculous mycobacteria infections27, 28, 29; these responses decline with effective antimycobacterial therapy.30, 31, 32 A significant decline in the ESAT-6 immune responses among subjects randomized to receive CLEAR (but not placebo) is provocative and of uncertain significance. It is unlikely that the decrease in ESAT-6 response in the CLEAR group is due to an immunosuppressant effect of one or more antibiotics in the treatment regimen because we previously reported improved immune function, including enhanced T-cell proliferative capacity and increased IL-2 and interferon-γ secretion, as well as augmented JAK-STAT signaling from sarcoidosis CD4+ T cells, following completion of the CLEAR regimen.11 The improvement in cellular immunity with CLEAR treatment of sarcoidosis could result in the augmented capacity to remove pathogenic microbial antigens such as ESAT-6. In addition, because the removal of microbial antigens such as ESAT-6 during treatment of mycobacterial infection reduces expression of profibrotic cytokines such as IL-17A, this mechanism may also mitigate the development of lung fibrosis during the treatment of sarcoidosis. The discrepancy between measurable declines in a virulence factor associated with active mycobacterial replication (ESAT-6) and the negative results of the current study remain unexplained.
It may be that mycobacterial antigens are important initial triggers of some cases of sarcoidosis, as suggested by persistence of mycobacterial antigens in sarcoidosis tissues,7 but viable infection is not integral to the perpetuation or progression of the disease. Also, because the study design did not obtain any samples to exclude the presence of infection in the subjects, it remains possible that the effects of CLEAR resulted in changes in the microbiome, which could then affect immune responses by changing the presence of microbial antigens. Future investigation regarding the impact of the CLEAR regimen on preventing further lung deterioration is warranted.
The current study did have some limitations. The number of subjects was relatively small. Twenty-five of the 97 patients were excluded from the per-protocol analysis, representing approximately 26% of the enrolled subjects. Twelve of those subjects (CLEAR, n = 8; placebo, n = 4) were excluded due to taking < 4 weeks of study medications, making it more difficult to assess the impact of 16 weeks of CLEAR therapy on the primary and secondary end points. Due to the pill burden and toxicities associated with a four-drug regimen, difficulty adhering to antimycobacterial therapy is well documented.33, 34, 35 Toxicities, such as myalgias and arthralgias from azithromycin and levofloxacin, as well as fatigue from rifabutin, may have affected the SGRQ score, masking our ability to clearly delineate an anti-sarcoidosis effect. Higher SGRQ scores were noted among CLEAR-treated patients experiencing these toxicities. Another limitation is the failure to include patients with disease for < 1 year. We did not include patients within 1 year of diagnosis because it was believed that differentiation of drug efficacy from spontaneous resolution would be too difficult. However, improvement in lung function among patients with TB is more likely if patients are < 40 years of age and do not have chronic sequelae.36 Future sarcoidosis clinical investigations should include patients within 1 year of their diagnosis, longer follow-up period assessment for potential steroid-sparing effect, and CT or PET scans. Several studies have shown that increased activity according to a PET scan is a useful predictor of treatment-responsive pulmonary sarcoidosis.37,38 PET scanning was not included in the current study because the information at time of study implementation was incomplete, and the cost of this as an exploratory analysis was prohibitive.
Conclusions
In a cohort of patients with progressive pulmonary sarcoidosis, the CLEAR therapy did not result in significant improvement in percent predicted FVC but, instead, was associated with significant declines in ESAT-6-specific immune responses.
Supplementary Data
e-Online Data
Acknowledgments
Author contributions: W. P. D. had full access to all the data following study completion and assumes full responsibility for the integrity of the data and the accuracy of the data analysis. W. P. D., D. A. C., R. P. B., and G.R.B. were responsible for conception and design; K. A., D. A. C., R. P. B., M. A. J., E. D. C., E. J., and A. G. performed experiments; T. D., G. D. A., G. R. B., and W. P. D. contributed to analysis and interpretation; and W. P. D, D. A. C., R. P. B., M. A. J., E. D. C., E. J., T. D., K. A., A. G., A. K., A.S., and G. R. B. drafted the manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. P. B. received personal fees from Actelion and from Mallinckrodt during the conduct of the study. None declared (W. P. D., D. A. C., M. A. J., E. D. C., E. J., G. D. A., T. D., K. A., A. G., A. K., A. S., G. R. B.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors are grateful for the support of the patients with sarcoidosis and nursing personnel for this investigation.
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
The contents of this article are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
FUNDING/SUPPORT: The publication was supported in part by CTSA award UL1 TR002243 from the 10.13039/100006108 National Center for Advancing Translational Sciences (G. R. B.); R01 HL117074 (W. P. D.); 10.13039/100004319 Pfizer Global Medical Grant Program 53232269; and the Pierce Foundation. | AZITHROMYCIN ANHYDROUS, ETHAMBUTOL HYDROCHLORIDE, LEVOFLOXACIN, RIFABUTIN | DrugsGivenReaction | CC BY-NC-ND | 33387486 | 18,762,907 | 2021-05 |
What was the dosage of drug 'AZITHROMYCIN ANHYDROUS'? | Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis.
A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.
The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.
In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.
The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).
Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.
Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1,2 Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3,4
Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5, 6, 7 In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7, 8, 9 Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8 as well as following administration of antimycobacterial therapy to patients with this disease.10 The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10,11 Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11 A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12 We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease.
Patients and Methods
Trial Design and Objectives
This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses.
Protocol Development and Oversight
The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13 This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen.
Interventions
Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269).
Population Eligibility and Randomization
Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1 Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least 5% on serial measurements over 24 months; (2) radiographic progression in chest imaging on side-by-side comparison; or (3) decline in dyspnea score, as measured by using the Transition Dyspnea Index. Prior to randomization, participants were assessed for peripheral immune responses to ESAT-6 or evidence of peripheral anergy as defined by absence of responses to phytohemagglutinin. If either of those conditions were present, the subject was enrolled. Finally, participants were required to have evidence of parenchymal or nodal disease on chest radiograph. Site-specific pulmonologists who were unaffiliated with the CLEAR trial read all site-specific lung function tests.
Sample size was calculated for the primary end point: change from baseline of FVC percent predicted. Using data from participants with chronic pulmonary sarcoidosis treated with infliximab,14 we obtained the SD of 7.7 for the primary end point. A sample size of 51 completed participants per arm was needed to have 90% power to detect a 5% difference in change of FVC percent predicted from baseline.
The major exclusion criteria were as follows:(1) Inability to obtain consent.
(2) Age < 18 years.
(3) Female participants of childbearing potential not willing to use one of the following methods of birth control for the duration of the study and 90 days following study completion: condoms, sponge, foams, jellies, diaphragm, nonhormonal intrauterine device, a vasectomized sole partner, or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test result at screening visit was required if the female subject was of childbearing potential.
(4) FVC predicted value < 45%.
(5) End-stage fibrotic pulmonary disease.
(6) Significant underlying liver disease.
(7) Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
(8) Allergy or intolerance to albuterol.
(9) Poor venous access for obtaining blood samples.
(10) History of active TB, close contact with a person with active TB within the 6 months prior to the screening visit, or a positive purified protein derivative skin test result.
(11) Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation (eg, respiratory, cardiac, neurologic, musculoskeletal, or seizure disorders).
(12) Use of an investigational drug within 30 days prior to screening or within five half-lives of the agent, whichever is longer.
(13) Currently receiving > 40 mg of prednisone.
(14) Alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal.
(15) Leukopenia, as defined by a WBC count < 3.0 cells/mm3 or absolute neutrophil count < 1,000/μL.
(16) Breastfeeding.
(17) Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis.
(18) If the patient is on immunomodulators, they must be on a regimen for 3 months or longer and on a stable dose for > 4 weeks.
(19) Family or personal history of long QT interval.
(20) Most recent nuclear medicine scan or echocardiogram (if performed) showing cardiac ejection fraction < 35%.
(21) Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotic, antiretroviral, or antifungal agents within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis.
(22) Any significant finding in the patient’s medical history or physical or psychiatric examination prior to or following randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol.
(23) Taking medications that, in the opinion of the investigator, would affect patient safety when taken with the antibiotics of the CLEAR regimen.
(24) History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit.
Patients were assigned to receive the CLEAR or placebo regimen by using a block randomization stratified according to site and use of prednisone ≥ 10 mg or not. Randomization lists were generated and distributed to site pharmacies by a statistician at Vanderbilt University Medical Center not associated with the study.
Measurement of Treatment Completion
Patients were requested to bring all remaining doses of every trial drug to each visit for pill counts. Treatment completion for the per-protocol analysis was defined as administration of at least 90% of the doses within 16 weeks.
Measurement of Safety During Treatment
At each follow-up visit, participants were questioned and examined for adverse events. Suspected adverse events were investigated, managed, and reported according to a standardized protocol. Information about suspected adverse events was reviewed and graded by the site-specific principal investigator and clinical coordinator. The severity of adverse events was judged according to the Common Toxicity Criteria for Adverse Events version 4.0. The events were categorized as follows: an adverse event that was not related to a trial drug; an adverse event of grade 1 or 2 that was related to a trial drug (not serious); an adverse event of grade 3 or 4 that was related to a trial drug (generally considered to lead to trial drug discontinuation if related to a trial drug); or a grade 5 event (death) that was related to a trial drug. Each adverse event resulting in organ impairment, hospitalization, or death was defined as a serious adverse event (SAE). An SAE was reported and reviewed by the institutional review board, as well as the four-member Data Safety Monitoring Board. The board provided oversight regarding safety for continuation of the study.
Oversight
This trial was approved by the Vanderbilt University Human Research Protection Program and by the institutional review board at each participating site. All the authors vouch for the accuracy and completeness of the data and analyses presented and for the compliance of the trial to the protocol.
Statistical Analysis
This randomized Phase II clinical trial was conducted to determine if CLEAR elicits a statistically significant (two-sided value P < .05) improvement in respiratory performance, the 6MWD, SGRQ, and immune responses against ESAT-6. Ninety-seven patients were randomized to treatment from May 5, 2014, to December 13, 2018, of whom 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were cleaned and locked for final analysis on April 18, 2019. The primary end point was baseline to 16-week change in preinhaler FVC as percent predicted. We defined the 16-week postrandomization FVC percent predicted value measurement as the value closest to 16 weeks from randomization within a window of 12 to 20 weeks from randomization.
The primary comparison between the CLEAR and placebo arms was conducted on an intention-to-treat (as randomized) basis among patients with both baseline and 16-week outcomes (N = 97). Unless otherwise stated, mean, SE, and comparative P values were estimates with multiple imputation using predictive mean matching with aregImpute, as previously described.15,16 The multiple imputation data sets were summarized according to Rubin’s rules.17 Unless otherwise noted, figures represent the mean change score ± the SE computed by using Rubin’s rules for imputed data. Change scores for secondary end points were compared by using the linear model formulation of the two-sample test between groups over 100 imputed data sets. The paired Student t test for multiply imputed data was used to compare baseline and 16-week change scores within each treatment group at 8 and 16 weeks. All analyses were repeated for a per-protocol population of patients (n = 72). Analysis of ESAT-6 and adverse events was not based on imputed data. The ESAT-6 analysis was the only within-group comparison and was conducted by using a Student paired t test, comparing baseline with 16-week values within their randomization cohort. The number of subjects experiencing an SAE and separately an adverse event (adverse events not including SAEs) was compared between treatment arms by using the paired or unpaired Student t test.
Results
Trial Participants
We screened 446 potential patients from May 2014 through December 2018, of whom 97 were enrolled and randomized to treatment (Fig 1). The most common reasons for exclusion from study participation were as follows: (1) significant comorbid conditions; (2) a history of a drug interaction between one of the CLEAR antibiotics with a medication that the patient was currently receiving; (3) patient declined to participate; (4) pulmonary hypertension treatment; (5) concerns for noncompliance with study visits; and (6) Scadding stage IV fibrosis detected on a chest radiograph.Figure 1 Consort Diagram of Phase IIB investigation of the efficacy of antimycobacterial therapy against progressive pulmonary sarcoidosis. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; LTBI = latent TB infection.
The demographic and clinical characteristics of all study participants according to their randomization group are shown in Table 1. Of the 97 enrolled subjects, baseline characteristics were well balanced across treatment arms. Approximately one-half of the population (n = 50 [52%]) was female, and the majority were White (n = 68 [70%]), with approximately one-third African American (n = 28 [29%]). A possible balance exception was sex (59% women in the placebo group and 44% women in the CLEAR group). Although not a planned analysis, analysis of covariance of sex (P = .996) with treatment group (P = .903) on nonimputed data, as with their interaction (P = .678), suggests no confounding by sex.Table 1 Patient Demographic Characteristics According to Therapeutic Regimen
Characteristic CLEAR Placebo Combined
(n = 49) (n = 48) (N = 97)
Age, mean ± SD, y 54.5 ± 9.8 54.5 ± 9.8 54.5 ± 10
Sex
Male 20 (41%) 27 (56%) 47 (48%)
Female 29 (59%) 21 (44%) 50 (52%)
Race
African American 15 (31%) 13 (27%) 28 (29%)
White 34 (69%) 34 (71%) 68 (70%)
Hawaiian or Pacific Islander 0 (0) 1 (2%) 1 (1%)
Ethnicity
Non-Hispanic/nor Latino 48 (98%) 46 (96%) 94 (97%)
Hispanic/Latino 1 (2%) 2 (4%) 3 (3%)
Baseline end points
Preinhaler FVC % 77.3 ± 13.7 75.5 ± 14.5 75.4 ± 14.1
6-min walk test, ma 416.2 ± 140.7 416.4 ± 105.2 416.3 ± 123.5
SGRQ activityb 57.7 ± 23.2 55.5 ± 24.5 56.6 ± 23.8
SGRQ impactb 34.8 ± 22.2 32.9 ± 19.8 33.8 ± 20.9
SGRQ symptomsb 53.9 ± 23.8 50.5 ± 19.3 52.2 ± 21.7
SGRQ totalb 44.9 ± 21.1 42.7 ± 18.7 43.8 ± 19.9
Immunosuppression
Patients on prednisone (mean dosage) 23 (47%) (10 mg) 19 (40%) (10 mg) 42 (43%) (10 mg)
Patients on a DMA 19 (39%) 17 (35%) 36 (37%)
Patients on a biologic agent 1 (2%) 1 (2%) 2 (4%)
Patients on prednisone plus a DMA or biologic agent 10 (20%) 6 (13%) 16 (16%)
Patients on any combination of prednisone, DMA, or biologic agent 11 (22%) 8 (17%) 19 (20%)
ESAT-6 positivity
Yes 39 (80%) 36 (75%) 75 (77%)
Equivocal 10 (20%) 12 (25%) 25 (23%)
CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; DMA = disease-modifying agent; ESAT-6 = early secreted antigenic target of 6 kDa.
a N = 48 for CLEAR and placebo groups.
b N = 48 and N = 47, for CLEAR and placebo groups, respectively.
The clinical data were analyzed via intention-to-treat and per protocol. No subjects were excluded from the intention-to-treat analysis. In the per-protocol analysis, 25 (12 in the active arm and 13 in the placebo arm) of the 97 patients were excluded because of failure to take > 4 weeks of the prescribed regimen (CLEAR, n = 8; placebo, n = 4), alteration in clinical immunosuppressive regimen while on study drugs (CLEAR, n = 1; placebo, n = 3), initiation of non-study antibiotics during study participation (CLEAR, n = 1; placebo, n = 3), and found to be receiving antibiotics with antimycobacterial therapy, such as trimethoprim-sulfamethoxazole, at the time of enrollment (CLEAR, n = 2; placebo, n = 3). The remaining 72 subjects were included in the per-protocol analysis.
Efficacy
In the intention-to-treat analysis, there were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between the CLEAR and placebo groups (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64) (Fig 2A, Table 2). Eight-eight patients experienced follow-up during the 12- to 20-week postrandomization window. Median (interquartile range) and mean ± SD of time to the date of FVC percent measurement was 17 (16.1-18) weeks and 17.5 ± 1.9 weeks, respectively. Time to primary end point measurement was equivalent between treatment groups, with a median (interquartile range) of 17 (16.2-18) weeks for placebo and 17.2 (16.2-18.0) weeks for CLEAR II patients. Mean ± SD values were 17.5 ± 1.9 and 17.4 ± 1.8. Evaluation of other physiological parameters, such as 6MWD (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = .91) revealed no statistically significant differences (Fig 2B). A negative change in the SGRQ score reflects an improvement in quality of life. The SRGQ did reveal statistically and clinically significant differences in favor of the placebo group (placebo, –7.97; CLEAR II, –1.52; P = .028, minimal clinically important difference = 4.0).Figure 2 A-B, Graphic depiction of intention-to-treat assessment of physiological parameters such as FVC and 6-min walk distance in 97 subjects with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, There were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between 49 CLEAR and 48 placebo subjects (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64). B, Evaluation of 6-min walk distance (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = 0.91) revealed no statistically significant difference. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Table 2 Physiological and Qualitative End Point Analyses
Variable Placebo CLEAR P Value
Intent-to-treat population
Preinhaler FVC % 0.02 ± 1.47 –1.06 ± 1.85 .640
6-min walk distance 12.40 ± 12.35 9.78 ± 19.31 .908
SGRQ activity –7.15 ± 3.28 –0.96 ± 2.87 .162
SGRQ impact –7.45 ± 2.64 –0.61 ± 2.78 .057
SGRQ symptoms –10.15 ± 3.45 –5.62 ± 3.22 .331
SGRQ total –7.97 ± 2.01 –1.52 ± 2.17 .028
Per-protocol group
Preinhaler FVC % 0.42 ± 1.48 –0.74 ± 1.75 .616
6-min walk distance 6.27 ± 11.99 36.35 ± 22.32 .242
SGRQ activity –4.25 ± 2.39 –1.45 ± 2.91 .458
SGRQ impact –7.97 ± 2.51 –1,10 ± 2.62 .061
SGRQ symptoms –9.78 ± 3.60 –8.07 ± 3.39 .730
SGRQ total –6.97 ± 2.13 –2.32 ± 2.32 .141
Imputed mean ± SE of baseline to 16-week differences in measurements. P values are from imputation-based two-sample Student t test. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; SGRQ = St. George’s Respiratory Questionnaire.
In the per-protocol analysis, 72 subjects were analyzed following removal of 25 patients prior to data analysis due to factors outlined in the protocol. Comparison of baseline vs week 16 end points of the remaining 72 patients revealed that there were no statistically differences in the primary end point (the change from baseline in percent predicted FVC) between 37 CLEAR-treated patients compared with 35 patients receiving placebo (CLEAR –0.74% vs placebo 0.42%; P = .62) (Fig 3A, Table 2). Evaluation of other physiological and qualitative end points revealed no significant differences; for example, there were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = .242) (Fig 3B). The SGRQ also revealed no significant differences in the total score between the groups (placebo, –6.9; CLEAR, –2.3; imputed two-sample Student t test, P = .14). CLEAR-treated patients had less improvement in activity, impact, and symptoms compared with patients receiving placebo.Figure 3 A-B, Graphic depiction of per-protocol assessment of physiologic parameters, such as FVC and placebo in 97 patients with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, Comparison of baseline vs week 16 end points of 72 subjects revealed that there were no statistically differences in the primary end point (change from baseline in percent predicted FVC) between 37 CLEAR subjects compared with 35 placebo subjects (CLEAR –0.74% vs placebo 0.42%; imputed two-sample Student t test, P = .62). B, Evaluation of 6-min walk distance revealed no significant difference among patients randomized to the CLEAR or the placebo regimen (36.4 m vs 6.3 m; imputed two-sample Student t test, P = .242). CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Although there was no significant baseline difference in ESAT-6-specific spot-forming units between the two groups (unpaired Student t test, P = .48) (Fig 4A), there was a significant difference in the spot-forming units following 16 weeks of therapy. There was no significant change in 38 subjects randomized to receive placebo (paired Student t test, P = .26) (Fig 4B); however, a significant decline in the ESAT-6 spot-forming units among the 31 patients randomized to the CLEAR regimen (paired Student t test, P = .0003) (Fig 4C). Only subjects for whom baseline and 16-week values were available were included in this analysis.Figure 4 Comparison of ESAT-6 immune responses at baseline (n = 69 subjects) (A), as well as baseline to 16 weeks among patients with sarcoidosis randomized to either the placebo (n = 38 subjects) (B) or CLEAR (n = 31 subjects) (C) regimen. ESAT-6 = early secreted antigenic target of 6 kDa; NS = not significant; PBMC = peripheral blood mononuclear cells; SFU = spot-forming units.
Safety
At each follow-up visit, participants were evaluated for adverse events. A total of 75 adverse events were noted in 39 subjects (e-Table 1). Any adverse event resulting in organ impairment, hospitalization, or death was defined as an SAE. The number of SAEs was similar for CLEAR (n = 4) and placebo (n = 3) (P = .72) (Table 3). Three of the four SAEs in the CLEAR cohort were believed to be related to study drugs; none was believed to be related in the placebo cohort. There were no deaths in this trial.Table 3 SAEs Throughout the Study
SAE Number Event Group Institution Date Anticipated Caused by Therapy
1 Leukopenia Active Cincinnati 08/14/2016 Yes Probable
2 Pneumonia Active Cincinnati 11/06/2014 Yes Probable
3 Neurosarcoidosis Active Vanderbilt 12/28/2016 No Not related
4 Hypotension Active AMC 01/29/2018 Yes Probable
5 Sepsis from abscess Placebo Cleveland 07/18/2017 No Not related
6 Postoperative infection Placebo Cleveland 11/14/2014 No Unlikely
7 Pneumonia Placebo Cleveland 06/04/2018 No Not related
AMC = Albany Medical College; SAE = severe adverse event.
Discussion
In this randomized, double-blind, placebo-controlled trial of CLEAR therapy, we observed no benefit from the study intervention on pulmonary function, for both the intention-to-treat and per-protocol analyses. Most secondary end points, such as 6MWD and SGRQ, showed no significant improvement from CLEAR, and SGRQ was worse at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated subjects, but no change was observed among those randomized to receive placebo (Figs 3, 4).
Although viable mycobacteria have been proposed to be causative agents for sarcoidosis, the current study provides no evidence to support that hypothesis. The current results are discordant from a randomized trial in which CLEAR therapy was beneficial for cutaneous sarcoidosis, and they also diverge from an uncontrolled report of CLEAR therapy.10,11 One explanation for the failure of CLEAR therapy is that the underlying hypothesis regarding the cause of sarcoidosis is incorrect. This explanation accords with the failure of prior studies to culture mycobacteria from sarcoidosis tissues.18,19
Other explanations for the failure of CLEAR therapy should also be considered. The inclusion criteria were designed to enroll a population with actively progressing sarcoidosis, but the precision of the longitudinal data supporting progression, and the long time window for demonstrating progression, are both problematic and may have biased the study population to include patients with relatively stable, adequately controlled disease.20 Progression in the placebo group on stable therapy would not be expected in a 16-week time frame. Active withdrawal of anti-sarcoidosis medications may be necessary to uncover relative treatment benefits if the effect size is modest, but this study required stable dosing throughout the treatment period. It is also possible that the treatment duration was too short to discern efficacy of therapy; medications such as methotrexate require up to 6 months to effect benefit in pulmonary sarcoidosis.21 Antibiotic therapy may not result in improved FVC; one study noted that these patients may continue to experience an FVC decline, but it occurs at a significantly lower rate than patients who were not successfully treated.22 Finally, FVC may be an insensitive marker of treatment effect; it has previously been shown to correlate poorly with symptoms and with chest imaging.23,24 However, the absence of any observable clinical benefits argues that the end point chosen here is likely not the cause of the negative result.
Immune responses against mycobacterial antigens, such as ESAT-6 and katG, are present in patients with active sarcoidosis disease.8,25,26 Independent investigators found that, using the ELISpot assay, antimycobacterial responses disappear with clinical resolution of sarcoidosis.8 Immune responses against ESAT-6 have also been detected with active or latent TB, as well as other nontuberculous mycobacteria infections27, 28, 29; these responses decline with effective antimycobacterial therapy.30, 31, 32 A significant decline in the ESAT-6 immune responses among subjects randomized to receive CLEAR (but not placebo) is provocative and of uncertain significance. It is unlikely that the decrease in ESAT-6 response in the CLEAR group is due to an immunosuppressant effect of one or more antibiotics in the treatment regimen because we previously reported improved immune function, including enhanced T-cell proliferative capacity and increased IL-2 and interferon-γ secretion, as well as augmented JAK-STAT signaling from sarcoidosis CD4+ T cells, following completion of the CLEAR regimen.11 The improvement in cellular immunity with CLEAR treatment of sarcoidosis could result in the augmented capacity to remove pathogenic microbial antigens such as ESAT-6. In addition, because the removal of microbial antigens such as ESAT-6 during treatment of mycobacterial infection reduces expression of profibrotic cytokines such as IL-17A, this mechanism may also mitigate the development of lung fibrosis during the treatment of sarcoidosis. The discrepancy between measurable declines in a virulence factor associated with active mycobacterial replication (ESAT-6) and the negative results of the current study remain unexplained.
It may be that mycobacterial antigens are important initial triggers of some cases of sarcoidosis, as suggested by persistence of mycobacterial antigens in sarcoidosis tissues,7 but viable infection is not integral to the perpetuation or progression of the disease. Also, because the study design did not obtain any samples to exclude the presence of infection in the subjects, it remains possible that the effects of CLEAR resulted in changes in the microbiome, which could then affect immune responses by changing the presence of microbial antigens. Future investigation regarding the impact of the CLEAR regimen on preventing further lung deterioration is warranted.
The current study did have some limitations. The number of subjects was relatively small. Twenty-five of the 97 patients were excluded from the per-protocol analysis, representing approximately 26% of the enrolled subjects. Twelve of those subjects (CLEAR, n = 8; placebo, n = 4) were excluded due to taking < 4 weeks of study medications, making it more difficult to assess the impact of 16 weeks of CLEAR therapy on the primary and secondary end points. Due to the pill burden and toxicities associated with a four-drug regimen, difficulty adhering to antimycobacterial therapy is well documented.33, 34, 35 Toxicities, such as myalgias and arthralgias from azithromycin and levofloxacin, as well as fatigue from rifabutin, may have affected the SGRQ score, masking our ability to clearly delineate an anti-sarcoidosis effect. Higher SGRQ scores were noted among CLEAR-treated patients experiencing these toxicities. Another limitation is the failure to include patients with disease for < 1 year. We did not include patients within 1 year of diagnosis because it was believed that differentiation of drug efficacy from spontaneous resolution would be too difficult. However, improvement in lung function among patients with TB is more likely if patients are < 40 years of age and do not have chronic sequelae.36 Future sarcoidosis clinical investigations should include patients within 1 year of their diagnosis, longer follow-up period assessment for potential steroid-sparing effect, and CT or PET scans. Several studies have shown that increased activity according to a PET scan is a useful predictor of treatment-responsive pulmonary sarcoidosis.37,38 PET scanning was not included in the current study because the information at time of study implementation was incomplete, and the cost of this as an exploratory analysis was prohibitive.
Conclusions
In a cohort of patients with progressive pulmonary sarcoidosis, the CLEAR therapy did not result in significant improvement in percent predicted FVC but, instead, was associated with significant declines in ESAT-6-specific immune responses.
Supplementary Data
e-Online Data
Acknowledgments
Author contributions: W. P. D. had full access to all the data following study completion and assumes full responsibility for the integrity of the data and the accuracy of the data analysis. W. P. D., D. A. C., R. P. B., and G.R.B. were responsible for conception and design; K. A., D. A. C., R. P. B., M. A. J., E. D. C., E. J., and A. G. performed experiments; T. D., G. D. A., G. R. B., and W. P. D. contributed to analysis and interpretation; and W. P. D, D. A. C., R. P. B., M. A. J., E. D. C., E. J., T. D., K. A., A. G., A. K., A.S., and G. R. B. drafted the manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. P. B. received personal fees from Actelion and from Mallinckrodt during the conduct of the study. None declared (W. P. D., D. A. C., M. A. J., E. D. C., E. J., G. D. A., T. D., K. A., A. G., A. K., A. S., G. R. B.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors are grateful for the support of the patients with sarcoidosis and nursing personnel for this investigation.
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
The contents of this article are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
FUNDING/SUPPORT: The publication was supported in part by CTSA award UL1 TR002243 from the 10.13039/100006108 National Center for Advancing Translational Sciences (G. R. B.); R01 HL117074 (W. P. D.); 10.13039/100004319 Pfizer Global Medical Grant Program 53232269; and the Pierce Foundation. | 250 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33387486 | 18,762,907 | 2021-05 |
What was the dosage of drug 'ETHAMBUTOL HYDROCHLORIDE'? | Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis.
A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.
The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.
In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.
The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).
Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.
Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1,2 Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3,4
Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5, 6, 7 In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7, 8, 9 Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8 as well as following administration of antimycobacterial therapy to patients with this disease.10 The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10,11 Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11 A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12 We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease.
Patients and Methods
Trial Design and Objectives
This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses.
Protocol Development and Oversight
The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13 This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen.
Interventions
Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269).
Population Eligibility and Randomization
Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1 Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least 5% on serial measurements over 24 months; (2) radiographic progression in chest imaging on side-by-side comparison; or (3) decline in dyspnea score, as measured by using the Transition Dyspnea Index. Prior to randomization, participants were assessed for peripheral immune responses to ESAT-6 or evidence of peripheral anergy as defined by absence of responses to phytohemagglutinin. If either of those conditions were present, the subject was enrolled. Finally, participants were required to have evidence of parenchymal or nodal disease on chest radiograph. Site-specific pulmonologists who were unaffiliated with the CLEAR trial read all site-specific lung function tests.
Sample size was calculated for the primary end point: change from baseline of FVC percent predicted. Using data from participants with chronic pulmonary sarcoidosis treated with infliximab,14 we obtained the SD of 7.7 for the primary end point. A sample size of 51 completed participants per arm was needed to have 90% power to detect a 5% difference in change of FVC percent predicted from baseline.
The major exclusion criteria were as follows:(1) Inability to obtain consent.
(2) Age < 18 years.
(3) Female participants of childbearing potential not willing to use one of the following methods of birth control for the duration of the study and 90 days following study completion: condoms, sponge, foams, jellies, diaphragm, nonhormonal intrauterine device, a vasectomized sole partner, or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test result at screening visit was required if the female subject was of childbearing potential.
(4) FVC predicted value < 45%.
(5) End-stage fibrotic pulmonary disease.
(6) Significant underlying liver disease.
(7) Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
(8) Allergy or intolerance to albuterol.
(9) Poor venous access for obtaining blood samples.
(10) History of active TB, close contact with a person with active TB within the 6 months prior to the screening visit, or a positive purified protein derivative skin test result.
(11) Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation (eg, respiratory, cardiac, neurologic, musculoskeletal, or seizure disorders).
(12) Use of an investigational drug within 30 days prior to screening or within five half-lives of the agent, whichever is longer.
(13) Currently receiving > 40 mg of prednisone.
(14) Alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal.
(15) Leukopenia, as defined by a WBC count < 3.0 cells/mm3 or absolute neutrophil count < 1,000/μL.
(16) Breastfeeding.
(17) Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis.
(18) If the patient is on immunomodulators, they must be on a regimen for 3 months or longer and on a stable dose for > 4 weeks.
(19) Family or personal history of long QT interval.
(20) Most recent nuclear medicine scan or echocardiogram (if performed) showing cardiac ejection fraction < 35%.
(21) Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotic, antiretroviral, or antifungal agents within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis.
(22) Any significant finding in the patient’s medical history or physical or psychiatric examination prior to or following randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol.
(23) Taking medications that, in the opinion of the investigator, would affect patient safety when taken with the antibiotics of the CLEAR regimen.
(24) History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit.
Patients were assigned to receive the CLEAR or placebo regimen by using a block randomization stratified according to site and use of prednisone ≥ 10 mg or not. Randomization lists were generated and distributed to site pharmacies by a statistician at Vanderbilt University Medical Center not associated with the study.
Measurement of Treatment Completion
Patients were requested to bring all remaining doses of every trial drug to each visit for pill counts. Treatment completion for the per-protocol analysis was defined as administration of at least 90% of the doses within 16 weeks.
Measurement of Safety During Treatment
At each follow-up visit, participants were questioned and examined for adverse events. Suspected adverse events were investigated, managed, and reported according to a standardized protocol. Information about suspected adverse events was reviewed and graded by the site-specific principal investigator and clinical coordinator. The severity of adverse events was judged according to the Common Toxicity Criteria for Adverse Events version 4.0. The events were categorized as follows: an adverse event that was not related to a trial drug; an adverse event of grade 1 or 2 that was related to a trial drug (not serious); an adverse event of grade 3 or 4 that was related to a trial drug (generally considered to lead to trial drug discontinuation if related to a trial drug); or a grade 5 event (death) that was related to a trial drug. Each adverse event resulting in organ impairment, hospitalization, or death was defined as a serious adverse event (SAE). An SAE was reported and reviewed by the institutional review board, as well as the four-member Data Safety Monitoring Board. The board provided oversight regarding safety for continuation of the study.
Oversight
This trial was approved by the Vanderbilt University Human Research Protection Program and by the institutional review board at each participating site. All the authors vouch for the accuracy and completeness of the data and analyses presented and for the compliance of the trial to the protocol.
Statistical Analysis
This randomized Phase II clinical trial was conducted to determine if CLEAR elicits a statistically significant (two-sided value P < .05) improvement in respiratory performance, the 6MWD, SGRQ, and immune responses against ESAT-6. Ninety-seven patients were randomized to treatment from May 5, 2014, to December 13, 2018, of whom 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were cleaned and locked for final analysis on April 18, 2019. The primary end point was baseline to 16-week change in preinhaler FVC as percent predicted. We defined the 16-week postrandomization FVC percent predicted value measurement as the value closest to 16 weeks from randomization within a window of 12 to 20 weeks from randomization.
The primary comparison between the CLEAR and placebo arms was conducted on an intention-to-treat (as randomized) basis among patients with both baseline and 16-week outcomes (N = 97). Unless otherwise stated, mean, SE, and comparative P values were estimates with multiple imputation using predictive mean matching with aregImpute, as previously described.15,16 The multiple imputation data sets were summarized according to Rubin’s rules.17 Unless otherwise noted, figures represent the mean change score ± the SE computed by using Rubin’s rules for imputed data. Change scores for secondary end points were compared by using the linear model formulation of the two-sample test between groups over 100 imputed data sets. The paired Student t test for multiply imputed data was used to compare baseline and 16-week change scores within each treatment group at 8 and 16 weeks. All analyses were repeated for a per-protocol population of patients (n = 72). Analysis of ESAT-6 and adverse events was not based on imputed data. The ESAT-6 analysis was the only within-group comparison and was conducted by using a Student paired t test, comparing baseline with 16-week values within their randomization cohort. The number of subjects experiencing an SAE and separately an adverse event (adverse events not including SAEs) was compared between treatment arms by using the paired or unpaired Student t test.
Results
Trial Participants
We screened 446 potential patients from May 2014 through December 2018, of whom 97 were enrolled and randomized to treatment (Fig 1). The most common reasons for exclusion from study participation were as follows: (1) significant comorbid conditions; (2) a history of a drug interaction between one of the CLEAR antibiotics with a medication that the patient was currently receiving; (3) patient declined to participate; (4) pulmonary hypertension treatment; (5) concerns for noncompliance with study visits; and (6) Scadding stage IV fibrosis detected on a chest radiograph.Figure 1 Consort Diagram of Phase IIB investigation of the efficacy of antimycobacterial therapy against progressive pulmonary sarcoidosis. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; LTBI = latent TB infection.
The demographic and clinical characteristics of all study participants according to their randomization group are shown in Table 1. Of the 97 enrolled subjects, baseline characteristics were well balanced across treatment arms. Approximately one-half of the population (n = 50 [52%]) was female, and the majority were White (n = 68 [70%]), with approximately one-third African American (n = 28 [29%]). A possible balance exception was sex (59% women in the placebo group and 44% women in the CLEAR group). Although not a planned analysis, analysis of covariance of sex (P = .996) with treatment group (P = .903) on nonimputed data, as with their interaction (P = .678), suggests no confounding by sex.Table 1 Patient Demographic Characteristics According to Therapeutic Regimen
Characteristic CLEAR Placebo Combined
(n = 49) (n = 48) (N = 97)
Age, mean ± SD, y 54.5 ± 9.8 54.5 ± 9.8 54.5 ± 10
Sex
Male 20 (41%) 27 (56%) 47 (48%)
Female 29 (59%) 21 (44%) 50 (52%)
Race
African American 15 (31%) 13 (27%) 28 (29%)
White 34 (69%) 34 (71%) 68 (70%)
Hawaiian or Pacific Islander 0 (0) 1 (2%) 1 (1%)
Ethnicity
Non-Hispanic/nor Latino 48 (98%) 46 (96%) 94 (97%)
Hispanic/Latino 1 (2%) 2 (4%) 3 (3%)
Baseline end points
Preinhaler FVC % 77.3 ± 13.7 75.5 ± 14.5 75.4 ± 14.1
6-min walk test, ma 416.2 ± 140.7 416.4 ± 105.2 416.3 ± 123.5
SGRQ activityb 57.7 ± 23.2 55.5 ± 24.5 56.6 ± 23.8
SGRQ impactb 34.8 ± 22.2 32.9 ± 19.8 33.8 ± 20.9
SGRQ symptomsb 53.9 ± 23.8 50.5 ± 19.3 52.2 ± 21.7
SGRQ totalb 44.9 ± 21.1 42.7 ± 18.7 43.8 ± 19.9
Immunosuppression
Patients on prednisone (mean dosage) 23 (47%) (10 mg) 19 (40%) (10 mg) 42 (43%) (10 mg)
Patients on a DMA 19 (39%) 17 (35%) 36 (37%)
Patients on a biologic agent 1 (2%) 1 (2%) 2 (4%)
Patients on prednisone plus a DMA or biologic agent 10 (20%) 6 (13%) 16 (16%)
Patients on any combination of prednisone, DMA, or biologic agent 11 (22%) 8 (17%) 19 (20%)
ESAT-6 positivity
Yes 39 (80%) 36 (75%) 75 (77%)
Equivocal 10 (20%) 12 (25%) 25 (23%)
CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; DMA = disease-modifying agent; ESAT-6 = early secreted antigenic target of 6 kDa.
a N = 48 for CLEAR and placebo groups.
b N = 48 and N = 47, for CLEAR and placebo groups, respectively.
The clinical data were analyzed via intention-to-treat and per protocol. No subjects were excluded from the intention-to-treat analysis. In the per-protocol analysis, 25 (12 in the active arm and 13 in the placebo arm) of the 97 patients were excluded because of failure to take > 4 weeks of the prescribed regimen (CLEAR, n = 8; placebo, n = 4), alteration in clinical immunosuppressive regimen while on study drugs (CLEAR, n = 1; placebo, n = 3), initiation of non-study antibiotics during study participation (CLEAR, n = 1; placebo, n = 3), and found to be receiving antibiotics with antimycobacterial therapy, such as trimethoprim-sulfamethoxazole, at the time of enrollment (CLEAR, n = 2; placebo, n = 3). The remaining 72 subjects were included in the per-protocol analysis.
Efficacy
In the intention-to-treat analysis, there were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between the CLEAR and placebo groups (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64) (Fig 2A, Table 2). Eight-eight patients experienced follow-up during the 12- to 20-week postrandomization window. Median (interquartile range) and mean ± SD of time to the date of FVC percent measurement was 17 (16.1-18) weeks and 17.5 ± 1.9 weeks, respectively. Time to primary end point measurement was equivalent between treatment groups, with a median (interquartile range) of 17 (16.2-18) weeks for placebo and 17.2 (16.2-18.0) weeks for CLEAR II patients. Mean ± SD values were 17.5 ± 1.9 and 17.4 ± 1.8. Evaluation of other physiological parameters, such as 6MWD (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = .91) revealed no statistically significant differences (Fig 2B). A negative change in the SGRQ score reflects an improvement in quality of life. The SRGQ did reveal statistically and clinically significant differences in favor of the placebo group (placebo, –7.97; CLEAR II, –1.52; P = .028, minimal clinically important difference = 4.0).Figure 2 A-B, Graphic depiction of intention-to-treat assessment of physiological parameters such as FVC and 6-min walk distance in 97 subjects with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, There were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between 49 CLEAR and 48 placebo subjects (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64). B, Evaluation of 6-min walk distance (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = 0.91) revealed no statistically significant difference. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Table 2 Physiological and Qualitative End Point Analyses
Variable Placebo CLEAR P Value
Intent-to-treat population
Preinhaler FVC % 0.02 ± 1.47 –1.06 ± 1.85 .640
6-min walk distance 12.40 ± 12.35 9.78 ± 19.31 .908
SGRQ activity –7.15 ± 3.28 –0.96 ± 2.87 .162
SGRQ impact –7.45 ± 2.64 –0.61 ± 2.78 .057
SGRQ symptoms –10.15 ± 3.45 –5.62 ± 3.22 .331
SGRQ total –7.97 ± 2.01 –1.52 ± 2.17 .028
Per-protocol group
Preinhaler FVC % 0.42 ± 1.48 –0.74 ± 1.75 .616
6-min walk distance 6.27 ± 11.99 36.35 ± 22.32 .242
SGRQ activity –4.25 ± 2.39 –1.45 ± 2.91 .458
SGRQ impact –7.97 ± 2.51 –1,10 ± 2.62 .061
SGRQ symptoms –9.78 ± 3.60 –8.07 ± 3.39 .730
SGRQ total –6.97 ± 2.13 –2.32 ± 2.32 .141
Imputed mean ± SE of baseline to 16-week differences in measurements. P values are from imputation-based two-sample Student t test. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; SGRQ = St. George’s Respiratory Questionnaire.
In the per-protocol analysis, 72 subjects were analyzed following removal of 25 patients prior to data analysis due to factors outlined in the protocol. Comparison of baseline vs week 16 end points of the remaining 72 patients revealed that there were no statistically differences in the primary end point (the change from baseline in percent predicted FVC) between 37 CLEAR-treated patients compared with 35 patients receiving placebo (CLEAR –0.74% vs placebo 0.42%; P = .62) (Fig 3A, Table 2). Evaluation of other physiological and qualitative end points revealed no significant differences; for example, there were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = .242) (Fig 3B). The SGRQ also revealed no significant differences in the total score between the groups (placebo, –6.9; CLEAR, –2.3; imputed two-sample Student t test, P = .14). CLEAR-treated patients had less improvement in activity, impact, and symptoms compared with patients receiving placebo.Figure 3 A-B, Graphic depiction of per-protocol assessment of physiologic parameters, such as FVC and placebo in 97 patients with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, Comparison of baseline vs week 16 end points of 72 subjects revealed that there were no statistically differences in the primary end point (change from baseline in percent predicted FVC) between 37 CLEAR subjects compared with 35 placebo subjects (CLEAR –0.74% vs placebo 0.42%; imputed two-sample Student t test, P = .62). B, Evaluation of 6-min walk distance revealed no significant difference among patients randomized to the CLEAR or the placebo regimen (36.4 m vs 6.3 m; imputed two-sample Student t test, P = .242). CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Although there was no significant baseline difference in ESAT-6-specific spot-forming units between the two groups (unpaired Student t test, P = .48) (Fig 4A), there was a significant difference in the spot-forming units following 16 weeks of therapy. There was no significant change in 38 subjects randomized to receive placebo (paired Student t test, P = .26) (Fig 4B); however, a significant decline in the ESAT-6 spot-forming units among the 31 patients randomized to the CLEAR regimen (paired Student t test, P = .0003) (Fig 4C). Only subjects for whom baseline and 16-week values were available were included in this analysis.Figure 4 Comparison of ESAT-6 immune responses at baseline (n = 69 subjects) (A), as well as baseline to 16 weeks among patients with sarcoidosis randomized to either the placebo (n = 38 subjects) (B) or CLEAR (n = 31 subjects) (C) regimen. ESAT-6 = early secreted antigenic target of 6 kDa; NS = not significant; PBMC = peripheral blood mononuclear cells; SFU = spot-forming units.
Safety
At each follow-up visit, participants were evaluated for adverse events. A total of 75 adverse events were noted in 39 subjects (e-Table 1). Any adverse event resulting in organ impairment, hospitalization, or death was defined as an SAE. The number of SAEs was similar for CLEAR (n = 4) and placebo (n = 3) (P = .72) (Table 3). Three of the four SAEs in the CLEAR cohort were believed to be related to study drugs; none was believed to be related in the placebo cohort. There were no deaths in this trial.Table 3 SAEs Throughout the Study
SAE Number Event Group Institution Date Anticipated Caused by Therapy
1 Leukopenia Active Cincinnati 08/14/2016 Yes Probable
2 Pneumonia Active Cincinnati 11/06/2014 Yes Probable
3 Neurosarcoidosis Active Vanderbilt 12/28/2016 No Not related
4 Hypotension Active AMC 01/29/2018 Yes Probable
5 Sepsis from abscess Placebo Cleveland 07/18/2017 No Not related
6 Postoperative infection Placebo Cleveland 11/14/2014 No Unlikely
7 Pneumonia Placebo Cleveland 06/04/2018 No Not related
AMC = Albany Medical College; SAE = severe adverse event.
Discussion
In this randomized, double-blind, placebo-controlled trial of CLEAR therapy, we observed no benefit from the study intervention on pulmonary function, for both the intention-to-treat and per-protocol analyses. Most secondary end points, such as 6MWD and SGRQ, showed no significant improvement from CLEAR, and SGRQ was worse at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated subjects, but no change was observed among those randomized to receive placebo (Figs 3, 4).
Although viable mycobacteria have been proposed to be causative agents for sarcoidosis, the current study provides no evidence to support that hypothesis. The current results are discordant from a randomized trial in which CLEAR therapy was beneficial for cutaneous sarcoidosis, and they also diverge from an uncontrolled report of CLEAR therapy.10,11 One explanation for the failure of CLEAR therapy is that the underlying hypothesis regarding the cause of sarcoidosis is incorrect. This explanation accords with the failure of prior studies to culture mycobacteria from sarcoidosis tissues.18,19
Other explanations for the failure of CLEAR therapy should also be considered. The inclusion criteria were designed to enroll a population with actively progressing sarcoidosis, but the precision of the longitudinal data supporting progression, and the long time window for demonstrating progression, are both problematic and may have biased the study population to include patients with relatively stable, adequately controlled disease.20 Progression in the placebo group on stable therapy would not be expected in a 16-week time frame. Active withdrawal of anti-sarcoidosis medications may be necessary to uncover relative treatment benefits if the effect size is modest, but this study required stable dosing throughout the treatment period. It is also possible that the treatment duration was too short to discern efficacy of therapy; medications such as methotrexate require up to 6 months to effect benefit in pulmonary sarcoidosis.21 Antibiotic therapy may not result in improved FVC; one study noted that these patients may continue to experience an FVC decline, but it occurs at a significantly lower rate than patients who were not successfully treated.22 Finally, FVC may be an insensitive marker of treatment effect; it has previously been shown to correlate poorly with symptoms and with chest imaging.23,24 However, the absence of any observable clinical benefits argues that the end point chosen here is likely not the cause of the negative result.
Immune responses against mycobacterial antigens, such as ESAT-6 and katG, are present in patients with active sarcoidosis disease.8,25,26 Independent investigators found that, using the ELISpot assay, antimycobacterial responses disappear with clinical resolution of sarcoidosis.8 Immune responses against ESAT-6 have also been detected with active or latent TB, as well as other nontuberculous mycobacteria infections27, 28, 29; these responses decline with effective antimycobacterial therapy.30, 31, 32 A significant decline in the ESAT-6 immune responses among subjects randomized to receive CLEAR (but not placebo) is provocative and of uncertain significance. It is unlikely that the decrease in ESAT-6 response in the CLEAR group is due to an immunosuppressant effect of one or more antibiotics in the treatment regimen because we previously reported improved immune function, including enhanced T-cell proliferative capacity and increased IL-2 and interferon-γ secretion, as well as augmented JAK-STAT signaling from sarcoidosis CD4+ T cells, following completion of the CLEAR regimen.11 The improvement in cellular immunity with CLEAR treatment of sarcoidosis could result in the augmented capacity to remove pathogenic microbial antigens such as ESAT-6. In addition, because the removal of microbial antigens such as ESAT-6 during treatment of mycobacterial infection reduces expression of profibrotic cytokines such as IL-17A, this mechanism may also mitigate the development of lung fibrosis during the treatment of sarcoidosis. The discrepancy between measurable declines in a virulence factor associated with active mycobacterial replication (ESAT-6) and the negative results of the current study remain unexplained.
It may be that mycobacterial antigens are important initial triggers of some cases of sarcoidosis, as suggested by persistence of mycobacterial antigens in sarcoidosis tissues,7 but viable infection is not integral to the perpetuation or progression of the disease. Also, because the study design did not obtain any samples to exclude the presence of infection in the subjects, it remains possible that the effects of CLEAR resulted in changes in the microbiome, which could then affect immune responses by changing the presence of microbial antigens. Future investigation regarding the impact of the CLEAR regimen on preventing further lung deterioration is warranted.
The current study did have some limitations. The number of subjects was relatively small. Twenty-five of the 97 patients were excluded from the per-protocol analysis, representing approximately 26% of the enrolled subjects. Twelve of those subjects (CLEAR, n = 8; placebo, n = 4) were excluded due to taking < 4 weeks of study medications, making it more difficult to assess the impact of 16 weeks of CLEAR therapy on the primary and secondary end points. Due to the pill burden and toxicities associated with a four-drug regimen, difficulty adhering to antimycobacterial therapy is well documented.33, 34, 35 Toxicities, such as myalgias and arthralgias from azithromycin and levofloxacin, as well as fatigue from rifabutin, may have affected the SGRQ score, masking our ability to clearly delineate an anti-sarcoidosis effect. Higher SGRQ scores were noted among CLEAR-treated patients experiencing these toxicities. Another limitation is the failure to include patients with disease for < 1 year. We did not include patients within 1 year of diagnosis because it was believed that differentiation of drug efficacy from spontaneous resolution would be too difficult. However, improvement in lung function among patients with TB is more likely if patients are < 40 years of age and do not have chronic sequelae.36 Future sarcoidosis clinical investigations should include patients within 1 year of their diagnosis, longer follow-up period assessment for potential steroid-sparing effect, and CT or PET scans. Several studies have shown that increased activity according to a PET scan is a useful predictor of treatment-responsive pulmonary sarcoidosis.37,38 PET scanning was not included in the current study because the information at time of study implementation was incomplete, and the cost of this as an exploratory analysis was prohibitive.
Conclusions
In a cohort of patients with progressive pulmonary sarcoidosis, the CLEAR therapy did not result in significant improvement in percent predicted FVC but, instead, was associated with significant declines in ESAT-6-specific immune responses.
Supplementary Data
e-Online Data
Acknowledgments
Author contributions: W. P. D. had full access to all the data following study completion and assumes full responsibility for the integrity of the data and the accuracy of the data analysis. W. P. D., D. A. C., R. P. B., and G.R.B. were responsible for conception and design; K. A., D. A. C., R. P. B., M. A. J., E. D. C., E. J., and A. G. performed experiments; T. D., G. D. A., G. R. B., and W. P. D. contributed to analysis and interpretation; and W. P. D, D. A. C., R. P. B., M. A. J., E. D. C., E. J., T. D., K. A., A. G., A. K., A.S., and G. R. B. drafted the manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. P. B. received personal fees from Actelion and from Mallinckrodt during the conduct of the study. None declared (W. P. D., D. A. C., M. A. J., E. D. C., E. J., G. D. A., T. D., K. A., A. G., A. K., A. S., G. R. B.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors are grateful for the support of the patients with sarcoidosis and nursing personnel for this investigation.
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
The contents of this article are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
FUNDING/SUPPORT: The publication was supported in part by CTSA award UL1 TR002243 from the 10.13039/100006108 National Center for Advancing Translational Sciences (G. R. B.); R01 HL117074 (W. P. D.); 10.13039/100004319 Pfizer Global Medical Grant Program 53232269; and the Pierce Foundation. | 1200 MG FOR }50KG; 800 MG FOR {50KG | DrugDosageText | CC BY-NC-ND | 33387486 | 18,762,907 | 2021-05 |
What was the dosage of drug 'LEVOFLOXACIN'? | Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis.
A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.
The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.
In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.
The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).
Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.
Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1,2 Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3,4
Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5, 6, 7 In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7, 8, 9 Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8 as well as following administration of antimycobacterial therapy to patients with this disease.10 The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10,11 Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11 A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12 We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease.
Patients and Methods
Trial Design and Objectives
This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses.
Protocol Development and Oversight
The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13 This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen.
Interventions
Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269).
Population Eligibility and Randomization
Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1 Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least 5% on serial measurements over 24 months; (2) radiographic progression in chest imaging on side-by-side comparison; or (3) decline in dyspnea score, as measured by using the Transition Dyspnea Index. Prior to randomization, participants were assessed for peripheral immune responses to ESAT-6 or evidence of peripheral anergy as defined by absence of responses to phytohemagglutinin. If either of those conditions were present, the subject was enrolled. Finally, participants were required to have evidence of parenchymal or nodal disease on chest radiograph. Site-specific pulmonologists who were unaffiliated with the CLEAR trial read all site-specific lung function tests.
Sample size was calculated for the primary end point: change from baseline of FVC percent predicted. Using data from participants with chronic pulmonary sarcoidosis treated with infliximab,14 we obtained the SD of 7.7 for the primary end point. A sample size of 51 completed participants per arm was needed to have 90% power to detect a 5% difference in change of FVC percent predicted from baseline.
The major exclusion criteria were as follows:(1) Inability to obtain consent.
(2) Age < 18 years.
(3) Female participants of childbearing potential not willing to use one of the following methods of birth control for the duration of the study and 90 days following study completion: condoms, sponge, foams, jellies, diaphragm, nonhormonal intrauterine device, a vasectomized sole partner, or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test result at screening visit was required if the female subject was of childbearing potential.
(4) FVC predicted value < 45%.
(5) End-stage fibrotic pulmonary disease.
(6) Significant underlying liver disease.
(7) Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
(8) Allergy or intolerance to albuterol.
(9) Poor venous access for obtaining blood samples.
(10) History of active TB, close contact with a person with active TB within the 6 months prior to the screening visit, or a positive purified protein derivative skin test result.
(11) Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation (eg, respiratory, cardiac, neurologic, musculoskeletal, or seizure disorders).
(12) Use of an investigational drug within 30 days prior to screening or within five half-lives of the agent, whichever is longer.
(13) Currently receiving > 40 mg of prednisone.
(14) Alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal.
(15) Leukopenia, as defined by a WBC count < 3.0 cells/mm3 or absolute neutrophil count < 1,000/μL.
(16) Breastfeeding.
(17) Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis.
(18) If the patient is on immunomodulators, they must be on a regimen for 3 months or longer and on a stable dose for > 4 weeks.
(19) Family or personal history of long QT interval.
(20) Most recent nuclear medicine scan or echocardiogram (if performed) showing cardiac ejection fraction < 35%.
(21) Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotic, antiretroviral, or antifungal agents within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis.
(22) Any significant finding in the patient’s medical history or physical or psychiatric examination prior to or following randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol.
(23) Taking medications that, in the opinion of the investigator, would affect patient safety when taken with the antibiotics of the CLEAR regimen.
(24) History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit.
Patients were assigned to receive the CLEAR or placebo regimen by using a block randomization stratified according to site and use of prednisone ≥ 10 mg or not. Randomization lists were generated and distributed to site pharmacies by a statistician at Vanderbilt University Medical Center not associated with the study.
Measurement of Treatment Completion
Patients were requested to bring all remaining doses of every trial drug to each visit for pill counts. Treatment completion for the per-protocol analysis was defined as administration of at least 90% of the doses within 16 weeks.
Measurement of Safety During Treatment
At each follow-up visit, participants were questioned and examined for adverse events. Suspected adverse events were investigated, managed, and reported according to a standardized protocol. Information about suspected adverse events was reviewed and graded by the site-specific principal investigator and clinical coordinator. The severity of adverse events was judged according to the Common Toxicity Criteria for Adverse Events version 4.0. The events were categorized as follows: an adverse event that was not related to a trial drug; an adverse event of grade 1 or 2 that was related to a trial drug (not serious); an adverse event of grade 3 or 4 that was related to a trial drug (generally considered to lead to trial drug discontinuation if related to a trial drug); or a grade 5 event (death) that was related to a trial drug. Each adverse event resulting in organ impairment, hospitalization, or death was defined as a serious adverse event (SAE). An SAE was reported and reviewed by the institutional review board, as well as the four-member Data Safety Monitoring Board. The board provided oversight regarding safety for continuation of the study.
Oversight
This trial was approved by the Vanderbilt University Human Research Protection Program and by the institutional review board at each participating site. All the authors vouch for the accuracy and completeness of the data and analyses presented and for the compliance of the trial to the protocol.
Statistical Analysis
This randomized Phase II clinical trial was conducted to determine if CLEAR elicits a statistically significant (two-sided value P < .05) improvement in respiratory performance, the 6MWD, SGRQ, and immune responses against ESAT-6. Ninety-seven patients were randomized to treatment from May 5, 2014, to December 13, 2018, of whom 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were cleaned and locked for final analysis on April 18, 2019. The primary end point was baseline to 16-week change in preinhaler FVC as percent predicted. We defined the 16-week postrandomization FVC percent predicted value measurement as the value closest to 16 weeks from randomization within a window of 12 to 20 weeks from randomization.
The primary comparison between the CLEAR and placebo arms was conducted on an intention-to-treat (as randomized) basis among patients with both baseline and 16-week outcomes (N = 97). Unless otherwise stated, mean, SE, and comparative P values were estimates with multiple imputation using predictive mean matching with aregImpute, as previously described.15,16 The multiple imputation data sets were summarized according to Rubin’s rules.17 Unless otherwise noted, figures represent the mean change score ± the SE computed by using Rubin’s rules for imputed data. Change scores for secondary end points were compared by using the linear model formulation of the two-sample test between groups over 100 imputed data sets. The paired Student t test for multiply imputed data was used to compare baseline and 16-week change scores within each treatment group at 8 and 16 weeks. All analyses were repeated for a per-protocol population of patients (n = 72). Analysis of ESAT-6 and adverse events was not based on imputed data. The ESAT-6 analysis was the only within-group comparison and was conducted by using a Student paired t test, comparing baseline with 16-week values within their randomization cohort. The number of subjects experiencing an SAE and separately an adverse event (adverse events not including SAEs) was compared between treatment arms by using the paired or unpaired Student t test.
Results
Trial Participants
We screened 446 potential patients from May 2014 through December 2018, of whom 97 were enrolled and randomized to treatment (Fig 1). The most common reasons for exclusion from study participation were as follows: (1) significant comorbid conditions; (2) a history of a drug interaction between one of the CLEAR antibiotics with a medication that the patient was currently receiving; (3) patient declined to participate; (4) pulmonary hypertension treatment; (5) concerns for noncompliance with study visits; and (6) Scadding stage IV fibrosis detected on a chest radiograph.Figure 1 Consort Diagram of Phase IIB investigation of the efficacy of antimycobacterial therapy against progressive pulmonary sarcoidosis. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; LTBI = latent TB infection.
The demographic and clinical characteristics of all study participants according to their randomization group are shown in Table 1. Of the 97 enrolled subjects, baseline characteristics were well balanced across treatment arms. Approximately one-half of the population (n = 50 [52%]) was female, and the majority were White (n = 68 [70%]), with approximately one-third African American (n = 28 [29%]). A possible balance exception was sex (59% women in the placebo group and 44% women in the CLEAR group). Although not a planned analysis, analysis of covariance of sex (P = .996) with treatment group (P = .903) on nonimputed data, as with their interaction (P = .678), suggests no confounding by sex.Table 1 Patient Demographic Characteristics According to Therapeutic Regimen
Characteristic CLEAR Placebo Combined
(n = 49) (n = 48) (N = 97)
Age, mean ± SD, y 54.5 ± 9.8 54.5 ± 9.8 54.5 ± 10
Sex
Male 20 (41%) 27 (56%) 47 (48%)
Female 29 (59%) 21 (44%) 50 (52%)
Race
African American 15 (31%) 13 (27%) 28 (29%)
White 34 (69%) 34 (71%) 68 (70%)
Hawaiian or Pacific Islander 0 (0) 1 (2%) 1 (1%)
Ethnicity
Non-Hispanic/nor Latino 48 (98%) 46 (96%) 94 (97%)
Hispanic/Latino 1 (2%) 2 (4%) 3 (3%)
Baseline end points
Preinhaler FVC % 77.3 ± 13.7 75.5 ± 14.5 75.4 ± 14.1
6-min walk test, ma 416.2 ± 140.7 416.4 ± 105.2 416.3 ± 123.5
SGRQ activityb 57.7 ± 23.2 55.5 ± 24.5 56.6 ± 23.8
SGRQ impactb 34.8 ± 22.2 32.9 ± 19.8 33.8 ± 20.9
SGRQ symptomsb 53.9 ± 23.8 50.5 ± 19.3 52.2 ± 21.7
SGRQ totalb 44.9 ± 21.1 42.7 ± 18.7 43.8 ± 19.9
Immunosuppression
Patients on prednisone (mean dosage) 23 (47%) (10 mg) 19 (40%) (10 mg) 42 (43%) (10 mg)
Patients on a DMA 19 (39%) 17 (35%) 36 (37%)
Patients on a biologic agent 1 (2%) 1 (2%) 2 (4%)
Patients on prednisone plus a DMA or biologic agent 10 (20%) 6 (13%) 16 (16%)
Patients on any combination of prednisone, DMA, or biologic agent 11 (22%) 8 (17%) 19 (20%)
ESAT-6 positivity
Yes 39 (80%) 36 (75%) 75 (77%)
Equivocal 10 (20%) 12 (25%) 25 (23%)
CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; DMA = disease-modifying agent; ESAT-6 = early secreted antigenic target of 6 kDa.
a N = 48 for CLEAR and placebo groups.
b N = 48 and N = 47, for CLEAR and placebo groups, respectively.
The clinical data were analyzed via intention-to-treat and per protocol. No subjects were excluded from the intention-to-treat analysis. In the per-protocol analysis, 25 (12 in the active arm and 13 in the placebo arm) of the 97 patients were excluded because of failure to take > 4 weeks of the prescribed regimen (CLEAR, n = 8; placebo, n = 4), alteration in clinical immunosuppressive regimen while on study drugs (CLEAR, n = 1; placebo, n = 3), initiation of non-study antibiotics during study participation (CLEAR, n = 1; placebo, n = 3), and found to be receiving antibiotics with antimycobacterial therapy, such as trimethoprim-sulfamethoxazole, at the time of enrollment (CLEAR, n = 2; placebo, n = 3). The remaining 72 subjects were included in the per-protocol analysis.
Efficacy
In the intention-to-treat analysis, there were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between the CLEAR and placebo groups (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64) (Fig 2A, Table 2). Eight-eight patients experienced follow-up during the 12- to 20-week postrandomization window. Median (interquartile range) and mean ± SD of time to the date of FVC percent measurement was 17 (16.1-18) weeks and 17.5 ± 1.9 weeks, respectively. Time to primary end point measurement was equivalent between treatment groups, with a median (interquartile range) of 17 (16.2-18) weeks for placebo and 17.2 (16.2-18.0) weeks for CLEAR II patients. Mean ± SD values were 17.5 ± 1.9 and 17.4 ± 1.8. Evaluation of other physiological parameters, such as 6MWD (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = .91) revealed no statistically significant differences (Fig 2B). A negative change in the SGRQ score reflects an improvement in quality of life. The SRGQ did reveal statistically and clinically significant differences in favor of the placebo group (placebo, –7.97; CLEAR II, –1.52; P = .028, minimal clinically important difference = 4.0).Figure 2 A-B, Graphic depiction of intention-to-treat assessment of physiological parameters such as FVC and 6-min walk distance in 97 subjects with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, There were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between 49 CLEAR and 48 placebo subjects (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64). B, Evaluation of 6-min walk distance (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = 0.91) revealed no statistically significant difference. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Table 2 Physiological and Qualitative End Point Analyses
Variable Placebo CLEAR P Value
Intent-to-treat population
Preinhaler FVC % 0.02 ± 1.47 –1.06 ± 1.85 .640
6-min walk distance 12.40 ± 12.35 9.78 ± 19.31 .908
SGRQ activity –7.15 ± 3.28 –0.96 ± 2.87 .162
SGRQ impact –7.45 ± 2.64 –0.61 ± 2.78 .057
SGRQ symptoms –10.15 ± 3.45 –5.62 ± 3.22 .331
SGRQ total –7.97 ± 2.01 –1.52 ± 2.17 .028
Per-protocol group
Preinhaler FVC % 0.42 ± 1.48 –0.74 ± 1.75 .616
6-min walk distance 6.27 ± 11.99 36.35 ± 22.32 .242
SGRQ activity –4.25 ± 2.39 –1.45 ± 2.91 .458
SGRQ impact –7.97 ± 2.51 –1,10 ± 2.62 .061
SGRQ symptoms –9.78 ± 3.60 –8.07 ± 3.39 .730
SGRQ total –6.97 ± 2.13 –2.32 ± 2.32 .141
Imputed mean ± SE of baseline to 16-week differences in measurements. P values are from imputation-based two-sample Student t test. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; SGRQ = St. George’s Respiratory Questionnaire.
In the per-protocol analysis, 72 subjects were analyzed following removal of 25 patients prior to data analysis due to factors outlined in the protocol. Comparison of baseline vs week 16 end points of the remaining 72 patients revealed that there were no statistically differences in the primary end point (the change from baseline in percent predicted FVC) between 37 CLEAR-treated patients compared with 35 patients receiving placebo (CLEAR –0.74% vs placebo 0.42%; P = .62) (Fig 3A, Table 2). Evaluation of other physiological and qualitative end points revealed no significant differences; for example, there were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = .242) (Fig 3B). The SGRQ also revealed no significant differences in the total score between the groups (placebo, –6.9; CLEAR, –2.3; imputed two-sample Student t test, P = .14). CLEAR-treated patients had less improvement in activity, impact, and symptoms compared with patients receiving placebo.Figure 3 A-B, Graphic depiction of per-protocol assessment of physiologic parameters, such as FVC and placebo in 97 patients with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, Comparison of baseline vs week 16 end points of 72 subjects revealed that there were no statistically differences in the primary end point (change from baseline in percent predicted FVC) between 37 CLEAR subjects compared with 35 placebo subjects (CLEAR –0.74% vs placebo 0.42%; imputed two-sample Student t test, P = .62). B, Evaluation of 6-min walk distance revealed no significant difference among patients randomized to the CLEAR or the placebo regimen (36.4 m vs 6.3 m; imputed two-sample Student t test, P = .242). CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Although there was no significant baseline difference in ESAT-6-specific spot-forming units between the two groups (unpaired Student t test, P = .48) (Fig 4A), there was a significant difference in the spot-forming units following 16 weeks of therapy. There was no significant change in 38 subjects randomized to receive placebo (paired Student t test, P = .26) (Fig 4B); however, a significant decline in the ESAT-6 spot-forming units among the 31 patients randomized to the CLEAR regimen (paired Student t test, P = .0003) (Fig 4C). Only subjects for whom baseline and 16-week values were available were included in this analysis.Figure 4 Comparison of ESAT-6 immune responses at baseline (n = 69 subjects) (A), as well as baseline to 16 weeks among patients with sarcoidosis randomized to either the placebo (n = 38 subjects) (B) or CLEAR (n = 31 subjects) (C) regimen. ESAT-6 = early secreted antigenic target of 6 kDa; NS = not significant; PBMC = peripheral blood mononuclear cells; SFU = spot-forming units.
Safety
At each follow-up visit, participants were evaluated for adverse events. A total of 75 adverse events were noted in 39 subjects (e-Table 1). Any adverse event resulting in organ impairment, hospitalization, or death was defined as an SAE. The number of SAEs was similar for CLEAR (n = 4) and placebo (n = 3) (P = .72) (Table 3). Three of the four SAEs in the CLEAR cohort were believed to be related to study drugs; none was believed to be related in the placebo cohort. There were no deaths in this trial.Table 3 SAEs Throughout the Study
SAE Number Event Group Institution Date Anticipated Caused by Therapy
1 Leukopenia Active Cincinnati 08/14/2016 Yes Probable
2 Pneumonia Active Cincinnati 11/06/2014 Yes Probable
3 Neurosarcoidosis Active Vanderbilt 12/28/2016 No Not related
4 Hypotension Active AMC 01/29/2018 Yes Probable
5 Sepsis from abscess Placebo Cleveland 07/18/2017 No Not related
6 Postoperative infection Placebo Cleveland 11/14/2014 No Unlikely
7 Pneumonia Placebo Cleveland 06/04/2018 No Not related
AMC = Albany Medical College; SAE = severe adverse event.
Discussion
In this randomized, double-blind, placebo-controlled trial of CLEAR therapy, we observed no benefit from the study intervention on pulmonary function, for both the intention-to-treat and per-protocol analyses. Most secondary end points, such as 6MWD and SGRQ, showed no significant improvement from CLEAR, and SGRQ was worse at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated subjects, but no change was observed among those randomized to receive placebo (Figs 3, 4).
Although viable mycobacteria have been proposed to be causative agents for sarcoidosis, the current study provides no evidence to support that hypothesis. The current results are discordant from a randomized trial in which CLEAR therapy was beneficial for cutaneous sarcoidosis, and they also diverge from an uncontrolled report of CLEAR therapy.10,11 One explanation for the failure of CLEAR therapy is that the underlying hypothesis regarding the cause of sarcoidosis is incorrect. This explanation accords with the failure of prior studies to culture mycobacteria from sarcoidosis tissues.18,19
Other explanations for the failure of CLEAR therapy should also be considered. The inclusion criteria were designed to enroll a population with actively progressing sarcoidosis, but the precision of the longitudinal data supporting progression, and the long time window for demonstrating progression, are both problematic and may have biased the study population to include patients with relatively stable, adequately controlled disease.20 Progression in the placebo group on stable therapy would not be expected in a 16-week time frame. Active withdrawal of anti-sarcoidosis medications may be necessary to uncover relative treatment benefits if the effect size is modest, but this study required stable dosing throughout the treatment period. It is also possible that the treatment duration was too short to discern efficacy of therapy; medications such as methotrexate require up to 6 months to effect benefit in pulmonary sarcoidosis.21 Antibiotic therapy may not result in improved FVC; one study noted that these patients may continue to experience an FVC decline, but it occurs at a significantly lower rate than patients who were not successfully treated.22 Finally, FVC may be an insensitive marker of treatment effect; it has previously been shown to correlate poorly with symptoms and with chest imaging.23,24 However, the absence of any observable clinical benefits argues that the end point chosen here is likely not the cause of the negative result.
Immune responses against mycobacterial antigens, such as ESAT-6 and katG, are present in patients with active sarcoidosis disease.8,25,26 Independent investigators found that, using the ELISpot assay, antimycobacterial responses disappear with clinical resolution of sarcoidosis.8 Immune responses against ESAT-6 have also been detected with active or latent TB, as well as other nontuberculous mycobacteria infections27, 28, 29; these responses decline with effective antimycobacterial therapy.30, 31, 32 A significant decline in the ESAT-6 immune responses among subjects randomized to receive CLEAR (but not placebo) is provocative and of uncertain significance. It is unlikely that the decrease in ESAT-6 response in the CLEAR group is due to an immunosuppressant effect of one or more antibiotics in the treatment regimen because we previously reported improved immune function, including enhanced T-cell proliferative capacity and increased IL-2 and interferon-γ secretion, as well as augmented JAK-STAT signaling from sarcoidosis CD4+ T cells, following completion of the CLEAR regimen.11 The improvement in cellular immunity with CLEAR treatment of sarcoidosis could result in the augmented capacity to remove pathogenic microbial antigens such as ESAT-6. In addition, because the removal of microbial antigens such as ESAT-6 during treatment of mycobacterial infection reduces expression of profibrotic cytokines such as IL-17A, this mechanism may also mitigate the development of lung fibrosis during the treatment of sarcoidosis. The discrepancy between measurable declines in a virulence factor associated with active mycobacterial replication (ESAT-6) and the negative results of the current study remain unexplained.
It may be that mycobacterial antigens are important initial triggers of some cases of sarcoidosis, as suggested by persistence of mycobacterial antigens in sarcoidosis tissues,7 but viable infection is not integral to the perpetuation or progression of the disease. Also, because the study design did not obtain any samples to exclude the presence of infection in the subjects, it remains possible that the effects of CLEAR resulted in changes in the microbiome, which could then affect immune responses by changing the presence of microbial antigens. Future investigation regarding the impact of the CLEAR regimen on preventing further lung deterioration is warranted.
The current study did have some limitations. The number of subjects was relatively small. Twenty-five of the 97 patients were excluded from the per-protocol analysis, representing approximately 26% of the enrolled subjects. Twelve of those subjects (CLEAR, n = 8; placebo, n = 4) were excluded due to taking < 4 weeks of study medications, making it more difficult to assess the impact of 16 weeks of CLEAR therapy on the primary and secondary end points. Due to the pill burden and toxicities associated with a four-drug regimen, difficulty adhering to antimycobacterial therapy is well documented.33, 34, 35 Toxicities, such as myalgias and arthralgias from azithromycin and levofloxacin, as well as fatigue from rifabutin, may have affected the SGRQ score, masking our ability to clearly delineate an anti-sarcoidosis effect. Higher SGRQ scores were noted among CLEAR-treated patients experiencing these toxicities. Another limitation is the failure to include patients with disease for < 1 year. We did not include patients within 1 year of diagnosis because it was believed that differentiation of drug efficacy from spontaneous resolution would be too difficult. However, improvement in lung function among patients with TB is more likely if patients are < 40 years of age and do not have chronic sequelae.36 Future sarcoidosis clinical investigations should include patients within 1 year of their diagnosis, longer follow-up period assessment for potential steroid-sparing effect, and CT or PET scans. Several studies have shown that increased activity according to a PET scan is a useful predictor of treatment-responsive pulmonary sarcoidosis.37,38 PET scanning was not included in the current study because the information at time of study implementation was incomplete, and the cost of this as an exploratory analysis was prohibitive.
Conclusions
In a cohort of patients with progressive pulmonary sarcoidosis, the CLEAR therapy did not result in significant improvement in percent predicted FVC but, instead, was associated with significant declines in ESAT-6-specific immune responses.
Supplementary Data
e-Online Data
Acknowledgments
Author contributions: W. P. D. had full access to all the data following study completion and assumes full responsibility for the integrity of the data and the accuracy of the data analysis. W. P. D., D. A. C., R. P. B., and G.R.B. were responsible for conception and design; K. A., D. A. C., R. P. B., M. A. J., E. D. C., E. J., and A. G. performed experiments; T. D., G. D. A., G. R. B., and W. P. D. contributed to analysis and interpretation; and W. P. D, D. A. C., R. P. B., M. A. J., E. D. C., E. J., T. D., K. A., A. G., A. K., A.S., and G. R. B. drafted the manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. P. B. received personal fees from Actelion and from Mallinckrodt during the conduct of the study. None declared (W. P. D., D. A. C., M. A. J., E. D. C., E. J., G. D. A., T. D., K. A., A. G., A. K., A. S., G. R. B.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors are grateful for the support of the patients with sarcoidosis and nursing personnel for this investigation.
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
The contents of this article are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
FUNDING/SUPPORT: The publication was supported in part by CTSA award UL1 TR002243 from the 10.13039/100006108 National Center for Advancing Translational Sciences (G. R. B.); R01 HL117074 (W. P. D.); 10.13039/100004319 Pfizer Global Medical Grant Program 53232269; and the Pierce Foundation. | 500 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33387486 | 18,762,907 | 2021-05 |
What was the dosage of drug 'RIFABUTIN'? | Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis.
A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.
The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.
In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.
The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).
Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis.
Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1,2 Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3,4
Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5, 6, 7 In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7, 8, 9 Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8 as well as following administration of antimycobacterial therapy to patients with this disease.10 The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10,11 Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11 A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12 We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease.
Patients and Methods
Trial Design and Objectives
This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses.
Protocol Development and Oversight
The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13 This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen.
Interventions
Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269).
Population Eligibility and Randomization
Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1 Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least 5% on serial measurements over 24 months; (2) radiographic progression in chest imaging on side-by-side comparison; or (3) decline in dyspnea score, as measured by using the Transition Dyspnea Index. Prior to randomization, participants were assessed for peripheral immune responses to ESAT-6 or evidence of peripheral anergy as defined by absence of responses to phytohemagglutinin. If either of those conditions were present, the subject was enrolled. Finally, participants were required to have evidence of parenchymal or nodal disease on chest radiograph. Site-specific pulmonologists who were unaffiliated with the CLEAR trial read all site-specific lung function tests.
Sample size was calculated for the primary end point: change from baseline of FVC percent predicted. Using data from participants with chronic pulmonary sarcoidosis treated with infliximab,14 we obtained the SD of 7.7 for the primary end point. A sample size of 51 completed participants per arm was needed to have 90% power to detect a 5% difference in change of FVC percent predicted from baseline.
The major exclusion criteria were as follows:(1) Inability to obtain consent.
(2) Age < 18 years.
(3) Female participants of childbearing potential not willing to use one of the following methods of birth control for the duration of the study and 90 days following study completion: condoms, sponge, foams, jellies, diaphragm, nonhormonal intrauterine device, a vasectomized sole partner, or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test result at screening visit was required if the female subject was of childbearing potential.
(4) FVC predicted value < 45%.
(5) End-stage fibrotic pulmonary disease.
(6) Significant underlying liver disease.
(7) Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
(8) Allergy or intolerance to albuterol.
(9) Poor venous access for obtaining blood samples.
(10) History of active TB, close contact with a person with active TB within the 6 months prior to the screening visit, or a positive purified protein derivative skin test result.
(11) Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation (eg, respiratory, cardiac, neurologic, musculoskeletal, or seizure disorders).
(12) Use of an investigational drug within 30 days prior to screening or within five half-lives of the agent, whichever is longer.
(13) Currently receiving > 40 mg of prednisone.
(14) Alanine aminotransferase or aspartate aminotransferase levels more than five times the upper limit of normal.
(15) Leukopenia, as defined by a WBC count < 3.0 cells/mm3 or absolute neutrophil count < 1,000/μL.
(16) Breastfeeding.
(17) Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis.
(18) If the patient is on immunomodulators, they must be on a regimen for 3 months or longer and on a stable dose for > 4 weeks.
(19) Family or personal history of long QT interval.
(20) Most recent nuclear medicine scan or echocardiogram (if performed) showing cardiac ejection fraction < 35%.
(21) Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotic, antiretroviral, or antifungal agents within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis.
(22) Any significant finding in the patient’s medical history or physical or psychiatric examination prior to or following randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol.
(23) Taking medications that, in the opinion of the investigator, would affect patient safety when taken with the antibiotics of the CLEAR regimen.
(24) History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit.
Patients were assigned to receive the CLEAR or placebo regimen by using a block randomization stratified according to site and use of prednisone ≥ 10 mg or not. Randomization lists were generated and distributed to site pharmacies by a statistician at Vanderbilt University Medical Center not associated with the study.
Measurement of Treatment Completion
Patients were requested to bring all remaining doses of every trial drug to each visit for pill counts. Treatment completion for the per-protocol analysis was defined as administration of at least 90% of the doses within 16 weeks.
Measurement of Safety During Treatment
At each follow-up visit, participants were questioned and examined for adverse events. Suspected adverse events were investigated, managed, and reported according to a standardized protocol. Information about suspected adverse events was reviewed and graded by the site-specific principal investigator and clinical coordinator. The severity of adverse events was judged according to the Common Toxicity Criteria for Adverse Events version 4.0. The events were categorized as follows: an adverse event that was not related to a trial drug; an adverse event of grade 1 or 2 that was related to a trial drug (not serious); an adverse event of grade 3 or 4 that was related to a trial drug (generally considered to lead to trial drug discontinuation if related to a trial drug); or a grade 5 event (death) that was related to a trial drug. Each adverse event resulting in organ impairment, hospitalization, or death was defined as a serious adverse event (SAE). An SAE was reported and reviewed by the institutional review board, as well as the four-member Data Safety Monitoring Board. The board provided oversight regarding safety for continuation of the study.
Oversight
This trial was approved by the Vanderbilt University Human Research Protection Program and by the institutional review board at each participating site. All the authors vouch for the accuracy and completeness of the data and analyses presented and for the compliance of the trial to the protocol.
Statistical Analysis
This randomized Phase II clinical trial was conducted to determine if CLEAR elicits a statistically significant (two-sided value P < .05) improvement in respiratory performance, the 6MWD, SGRQ, and immune responses against ESAT-6. Ninety-seven patients were randomized to treatment from May 5, 2014, to December 13, 2018, of whom 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were cleaned and locked for final analysis on April 18, 2019. The primary end point was baseline to 16-week change in preinhaler FVC as percent predicted. We defined the 16-week postrandomization FVC percent predicted value measurement as the value closest to 16 weeks from randomization within a window of 12 to 20 weeks from randomization.
The primary comparison between the CLEAR and placebo arms was conducted on an intention-to-treat (as randomized) basis among patients with both baseline and 16-week outcomes (N = 97). Unless otherwise stated, mean, SE, and comparative P values were estimates with multiple imputation using predictive mean matching with aregImpute, as previously described.15,16 The multiple imputation data sets were summarized according to Rubin’s rules.17 Unless otherwise noted, figures represent the mean change score ± the SE computed by using Rubin’s rules for imputed data. Change scores for secondary end points were compared by using the linear model formulation of the two-sample test between groups over 100 imputed data sets. The paired Student t test for multiply imputed data was used to compare baseline and 16-week change scores within each treatment group at 8 and 16 weeks. All analyses were repeated for a per-protocol population of patients (n = 72). Analysis of ESAT-6 and adverse events was not based on imputed data. The ESAT-6 analysis was the only within-group comparison and was conducted by using a Student paired t test, comparing baseline with 16-week values within their randomization cohort. The number of subjects experiencing an SAE and separately an adverse event (adverse events not including SAEs) was compared between treatment arms by using the paired or unpaired Student t test.
Results
Trial Participants
We screened 446 potential patients from May 2014 through December 2018, of whom 97 were enrolled and randomized to treatment (Fig 1). The most common reasons for exclusion from study participation were as follows: (1) significant comorbid conditions; (2) a history of a drug interaction between one of the CLEAR antibiotics with a medication that the patient was currently receiving; (3) patient declined to participate; (4) pulmonary hypertension treatment; (5) concerns for noncompliance with study visits; and (6) Scadding stage IV fibrosis detected on a chest radiograph.Figure 1 Consort Diagram of Phase IIB investigation of the efficacy of antimycobacterial therapy against progressive pulmonary sarcoidosis. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; LTBI = latent TB infection.
The demographic and clinical characteristics of all study participants according to their randomization group are shown in Table 1. Of the 97 enrolled subjects, baseline characteristics were well balanced across treatment arms. Approximately one-half of the population (n = 50 [52%]) was female, and the majority were White (n = 68 [70%]), with approximately one-third African American (n = 28 [29%]). A possible balance exception was sex (59% women in the placebo group and 44% women in the CLEAR group). Although not a planned analysis, analysis of covariance of sex (P = .996) with treatment group (P = .903) on nonimputed data, as with their interaction (P = .678), suggests no confounding by sex.Table 1 Patient Demographic Characteristics According to Therapeutic Regimen
Characteristic CLEAR Placebo Combined
(n = 49) (n = 48) (N = 97)
Age, mean ± SD, y 54.5 ± 9.8 54.5 ± 9.8 54.5 ± 10
Sex
Male 20 (41%) 27 (56%) 47 (48%)
Female 29 (59%) 21 (44%) 50 (52%)
Race
African American 15 (31%) 13 (27%) 28 (29%)
White 34 (69%) 34 (71%) 68 (70%)
Hawaiian or Pacific Islander 0 (0) 1 (2%) 1 (1%)
Ethnicity
Non-Hispanic/nor Latino 48 (98%) 46 (96%) 94 (97%)
Hispanic/Latino 1 (2%) 2 (4%) 3 (3%)
Baseline end points
Preinhaler FVC % 77.3 ± 13.7 75.5 ± 14.5 75.4 ± 14.1
6-min walk test, ma 416.2 ± 140.7 416.4 ± 105.2 416.3 ± 123.5
SGRQ activityb 57.7 ± 23.2 55.5 ± 24.5 56.6 ± 23.8
SGRQ impactb 34.8 ± 22.2 32.9 ± 19.8 33.8 ± 20.9
SGRQ symptomsb 53.9 ± 23.8 50.5 ± 19.3 52.2 ± 21.7
SGRQ totalb 44.9 ± 21.1 42.7 ± 18.7 43.8 ± 19.9
Immunosuppression
Patients on prednisone (mean dosage) 23 (47%) (10 mg) 19 (40%) (10 mg) 42 (43%) (10 mg)
Patients on a DMA 19 (39%) 17 (35%) 36 (37%)
Patients on a biologic agent 1 (2%) 1 (2%) 2 (4%)
Patients on prednisone plus a DMA or biologic agent 10 (20%) 6 (13%) 16 (16%)
Patients on any combination of prednisone, DMA, or biologic agent 11 (22%) 8 (17%) 19 (20%)
ESAT-6 positivity
Yes 39 (80%) 36 (75%) 75 (77%)
Equivocal 10 (20%) 12 (25%) 25 (23%)
CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; DMA = disease-modifying agent; ESAT-6 = early secreted antigenic target of 6 kDa.
a N = 48 for CLEAR and placebo groups.
b N = 48 and N = 47, for CLEAR and placebo groups, respectively.
The clinical data were analyzed via intention-to-treat and per protocol. No subjects were excluded from the intention-to-treat analysis. In the per-protocol analysis, 25 (12 in the active arm and 13 in the placebo arm) of the 97 patients were excluded because of failure to take > 4 weeks of the prescribed regimen (CLEAR, n = 8; placebo, n = 4), alteration in clinical immunosuppressive regimen while on study drugs (CLEAR, n = 1; placebo, n = 3), initiation of non-study antibiotics during study participation (CLEAR, n = 1; placebo, n = 3), and found to be receiving antibiotics with antimycobacterial therapy, such as trimethoprim-sulfamethoxazole, at the time of enrollment (CLEAR, n = 2; placebo, n = 3). The remaining 72 subjects were included in the per-protocol analysis.
Efficacy
In the intention-to-treat analysis, there were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between the CLEAR and placebo groups (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64) (Fig 2A, Table 2). Eight-eight patients experienced follow-up during the 12- to 20-week postrandomization window. Median (interquartile range) and mean ± SD of time to the date of FVC percent measurement was 17 (16.1-18) weeks and 17.5 ± 1.9 weeks, respectively. Time to primary end point measurement was equivalent between treatment groups, with a median (interquartile range) of 17 (16.2-18) weeks for placebo and 17.2 (16.2-18.0) weeks for CLEAR II patients. Mean ± SD values were 17.5 ± 1.9 and 17.4 ± 1.8. Evaluation of other physiological parameters, such as 6MWD (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = .91) revealed no statistically significant differences (Fig 2B). A negative change in the SGRQ score reflects an improvement in quality of life. The SRGQ did reveal statistically and clinically significant differences in favor of the placebo group (placebo, –7.97; CLEAR II, –1.52; P = .028, minimal clinically important difference = 4.0).Figure 2 A-B, Graphic depiction of intention-to-treat assessment of physiological parameters such as FVC and 6-min walk distance in 97 subjects with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, There were no statistically significant differences in the primary end point (change from baseline to week 16 in pre-bronchodilator percent predicted FVC) between 49 CLEAR and 48 placebo subjects (CLEAR –1.06% vs placebo 0.02%; imputed two-sample Student t test, P = .64). B, Evaluation of 6-min walk distance (placebo, 12.4 m; CLEAR, 9.8 m; imputed two-sample Student t test, P = 0.91) revealed no statistically significant difference. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Table 2 Physiological and Qualitative End Point Analyses
Variable Placebo CLEAR P Value
Intent-to-treat population
Preinhaler FVC % 0.02 ± 1.47 –1.06 ± 1.85 .640
6-min walk distance 12.40 ± 12.35 9.78 ± 19.31 .908
SGRQ activity –7.15 ± 3.28 –0.96 ± 2.87 .162
SGRQ impact –7.45 ± 2.64 –0.61 ± 2.78 .057
SGRQ symptoms –10.15 ± 3.45 –5.62 ± 3.22 .331
SGRQ total –7.97 ± 2.01 –1.52 ± 2.17 .028
Per-protocol group
Preinhaler FVC % 0.42 ± 1.48 –0.74 ± 1.75 .616
6-min walk distance 6.27 ± 11.99 36.35 ± 22.32 .242
SGRQ activity –4.25 ± 2.39 –1.45 ± 2.91 .458
SGRQ impact –7.97 ± 2.51 –1,10 ± 2.62 .061
SGRQ symptoms –9.78 ± 3.60 –8.07 ± 3.39 .730
SGRQ total –6.97 ± 2.13 –2.32 ± 2.32 .141
Imputed mean ± SE of baseline to 16-week differences in measurements. P values are from imputation-based two-sample Student t test. CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin; SGRQ = St. George’s Respiratory Questionnaire.
In the per-protocol analysis, 72 subjects were analyzed following removal of 25 patients prior to data analysis due to factors outlined in the protocol. Comparison of baseline vs week 16 end points of the remaining 72 patients revealed that there were no statistically differences in the primary end point (the change from baseline in percent predicted FVC) between 37 CLEAR-treated patients compared with 35 patients receiving placebo (CLEAR –0.74% vs placebo 0.42%; P = .62) (Fig 3A, Table 2). Evaluation of other physiological and qualitative end points revealed no significant differences; for example, there were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = .242) (Fig 3B). The SGRQ also revealed no significant differences in the total score between the groups (placebo, –6.9; CLEAR, –2.3; imputed two-sample Student t test, P = .14). CLEAR-treated patients had less improvement in activity, impact, and symptoms compared with patients receiving placebo.Figure 3 A-B, Graphic depiction of per-protocol assessment of physiologic parameters, such as FVC and placebo in 97 patients with sarcoidosis randomized to either the CLEAR regimen (active) or placebo. A, Comparison of baseline vs week 16 end points of 72 subjects revealed that there were no statistically differences in the primary end point (change from baseline in percent predicted FVC) between 37 CLEAR subjects compared with 35 placebo subjects (CLEAR –0.74% vs placebo 0.42%; imputed two-sample Student t test, P = .62). B, Evaluation of 6-min walk distance revealed no significant difference among patients randomized to the CLEAR or the placebo regimen (36.4 m vs 6.3 m; imputed two-sample Student t test, P = .242). CLEAR = concomitant Levaquin, ethambutol, azithromycin, and rifamycin.
Although there was no significant baseline difference in ESAT-6-specific spot-forming units between the two groups (unpaired Student t test, P = .48) (Fig 4A), there was a significant difference in the spot-forming units following 16 weeks of therapy. There was no significant change in 38 subjects randomized to receive placebo (paired Student t test, P = .26) (Fig 4B); however, a significant decline in the ESAT-6 spot-forming units among the 31 patients randomized to the CLEAR regimen (paired Student t test, P = .0003) (Fig 4C). Only subjects for whom baseline and 16-week values were available were included in this analysis.Figure 4 Comparison of ESAT-6 immune responses at baseline (n = 69 subjects) (A), as well as baseline to 16 weeks among patients with sarcoidosis randomized to either the placebo (n = 38 subjects) (B) or CLEAR (n = 31 subjects) (C) regimen. ESAT-6 = early secreted antigenic target of 6 kDa; NS = not significant; PBMC = peripheral blood mononuclear cells; SFU = spot-forming units.
Safety
At each follow-up visit, participants were evaluated for adverse events. A total of 75 adverse events were noted in 39 subjects (e-Table 1). Any adverse event resulting in organ impairment, hospitalization, or death was defined as an SAE. The number of SAEs was similar for CLEAR (n = 4) and placebo (n = 3) (P = .72) (Table 3). Three of the four SAEs in the CLEAR cohort were believed to be related to study drugs; none was believed to be related in the placebo cohort. There were no deaths in this trial.Table 3 SAEs Throughout the Study
SAE Number Event Group Institution Date Anticipated Caused by Therapy
1 Leukopenia Active Cincinnati 08/14/2016 Yes Probable
2 Pneumonia Active Cincinnati 11/06/2014 Yes Probable
3 Neurosarcoidosis Active Vanderbilt 12/28/2016 No Not related
4 Hypotension Active AMC 01/29/2018 Yes Probable
5 Sepsis from abscess Placebo Cleveland 07/18/2017 No Not related
6 Postoperative infection Placebo Cleveland 11/14/2014 No Unlikely
7 Pneumonia Placebo Cleveland 06/04/2018 No Not related
AMC = Albany Medical College; SAE = severe adverse event.
Discussion
In this randomized, double-blind, placebo-controlled trial of CLEAR therapy, we observed no benefit from the study intervention on pulmonary function, for both the intention-to-treat and per-protocol analyses. Most secondary end points, such as 6MWD and SGRQ, showed no significant improvement from CLEAR, and SGRQ was worse at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated subjects, but no change was observed among those randomized to receive placebo (Figs 3, 4).
Although viable mycobacteria have been proposed to be causative agents for sarcoidosis, the current study provides no evidence to support that hypothesis. The current results are discordant from a randomized trial in which CLEAR therapy was beneficial for cutaneous sarcoidosis, and they also diverge from an uncontrolled report of CLEAR therapy.10,11 One explanation for the failure of CLEAR therapy is that the underlying hypothesis regarding the cause of sarcoidosis is incorrect. This explanation accords with the failure of prior studies to culture mycobacteria from sarcoidosis tissues.18,19
Other explanations for the failure of CLEAR therapy should also be considered. The inclusion criteria were designed to enroll a population with actively progressing sarcoidosis, but the precision of the longitudinal data supporting progression, and the long time window for demonstrating progression, are both problematic and may have biased the study population to include patients with relatively stable, adequately controlled disease.20 Progression in the placebo group on stable therapy would not be expected in a 16-week time frame. Active withdrawal of anti-sarcoidosis medications may be necessary to uncover relative treatment benefits if the effect size is modest, but this study required stable dosing throughout the treatment period. It is also possible that the treatment duration was too short to discern efficacy of therapy; medications such as methotrexate require up to 6 months to effect benefit in pulmonary sarcoidosis.21 Antibiotic therapy may not result in improved FVC; one study noted that these patients may continue to experience an FVC decline, but it occurs at a significantly lower rate than patients who were not successfully treated.22 Finally, FVC may be an insensitive marker of treatment effect; it has previously been shown to correlate poorly with symptoms and with chest imaging.23,24 However, the absence of any observable clinical benefits argues that the end point chosen here is likely not the cause of the negative result.
Immune responses against mycobacterial antigens, such as ESAT-6 and katG, are present in patients with active sarcoidosis disease.8,25,26 Independent investigators found that, using the ELISpot assay, antimycobacterial responses disappear with clinical resolution of sarcoidosis.8 Immune responses against ESAT-6 have also been detected with active or latent TB, as well as other nontuberculous mycobacteria infections27, 28, 29; these responses decline with effective antimycobacterial therapy.30, 31, 32 A significant decline in the ESAT-6 immune responses among subjects randomized to receive CLEAR (but not placebo) is provocative and of uncertain significance. It is unlikely that the decrease in ESAT-6 response in the CLEAR group is due to an immunosuppressant effect of one or more antibiotics in the treatment regimen because we previously reported improved immune function, including enhanced T-cell proliferative capacity and increased IL-2 and interferon-γ secretion, as well as augmented JAK-STAT signaling from sarcoidosis CD4+ T cells, following completion of the CLEAR regimen.11 The improvement in cellular immunity with CLEAR treatment of sarcoidosis could result in the augmented capacity to remove pathogenic microbial antigens such as ESAT-6. In addition, because the removal of microbial antigens such as ESAT-6 during treatment of mycobacterial infection reduces expression of profibrotic cytokines such as IL-17A, this mechanism may also mitigate the development of lung fibrosis during the treatment of sarcoidosis. The discrepancy between measurable declines in a virulence factor associated with active mycobacterial replication (ESAT-6) and the negative results of the current study remain unexplained.
It may be that mycobacterial antigens are important initial triggers of some cases of sarcoidosis, as suggested by persistence of mycobacterial antigens in sarcoidosis tissues,7 but viable infection is not integral to the perpetuation or progression of the disease. Also, because the study design did not obtain any samples to exclude the presence of infection in the subjects, it remains possible that the effects of CLEAR resulted in changes in the microbiome, which could then affect immune responses by changing the presence of microbial antigens. Future investigation regarding the impact of the CLEAR regimen on preventing further lung deterioration is warranted.
The current study did have some limitations. The number of subjects was relatively small. Twenty-five of the 97 patients were excluded from the per-protocol analysis, representing approximately 26% of the enrolled subjects. Twelve of those subjects (CLEAR, n = 8; placebo, n = 4) were excluded due to taking < 4 weeks of study medications, making it more difficult to assess the impact of 16 weeks of CLEAR therapy on the primary and secondary end points. Due to the pill burden and toxicities associated with a four-drug regimen, difficulty adhering to antimycobacterial therapy is well documented.33, 34, 35 Toxicities, such as myalgias and arthralgias from azithromycin and levofloxacin, as well as fatigue from rifabutin, may have affected the SGRQ score, masking our ability to clearly delineate an anti-sarcoidosis effect. Higher SGRQ scores were noted among CLEAR-treated patients experiencing these toxicities. Another limitation is the failure to include patients with disease for < 1 year. We did not include patients within 1 year of diagnosis because it was believed that differentiation of drug efficacy from spontaneous resolution would be too difficult. However, improvement in lung function among patients with TB is more likely if patients are < 40 years of age and do not have chronic sequelae.36 Future sarcoidosis clinical investigations should include patients within 1 year of their diagnosis, longer follow-up period assessment for potential steroid-sparing effect, and CT or PET scans. Several studies have shown that increased activity according to a PET scan is a useful predictor of treatment-responsive pulmonary sarcoidosis.37,38 PET scanning was not included in the current study because the information at time of study implementation was incomplete, and the cost of this as an exploratory analysis was prohibitive.
Conclusions
In a cohort of patients with progressive pulmonary sarcoidosis, the CLEAR therapy did not result in significant improvement in percent predicted FVC but, instead, was associated with significant declines in ESAT-6-specific immune responses.
Supplementary Data
e-Online Data
Acknowledgments
Author contributions: W. P. D. had full access to all the data following study completion and assumes full responsibility for the integrity of the data and the accuracy of the data analysis. W. P. D., D. A. C., R. P. B., and G.R.B. were responsible for conception and design; K. A., D. A. C., R. P. B., M. A. J., E. D. C., E. J., and A. G. performed experiments; T. D., G. D. A., G. R. B., and W. P. D. contributed to analysis and interpretation; and W. P. D, D. A. C., R. P. B., M. A. J., E. D. C., E. J., T. D., K. A., A. G., A. K., A.S., and G. R. B. drafted the manuscript for important intellectual content.
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. P. B. received personal fees from Actelion and from Mallinckrodt during the conduct of the study. None declared (W. P. D., D. A. C., M. A. J., E. D. C., E. J., G. D. A., T. D., K. A., A. G., A. K., A. S., G. R. B.).
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: The authors are grateful for the support of the patients with sarcoidosis and nursing personnel for this investigation.
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
The contents of this article are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
FUNDING/SUPPORT: The publication was supported in part by CTSA award UL1 TR002243 from the 10.13039/100006108 National Center for Advancing Translational Sciences (G. R. B.); R01 HL117074 (W. P. D.); 10.13039/100004319 Pfizer Global Medical Grant Program 53232269; and the Pierce Foundation. | 300 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33387486 | 18,762,907 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diffuse large B-cell lymphoma'. | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | METHOTREXATE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33388058 | 18,775,470 | 2021-01-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epstein Barr virus positive mucocutaneous ulcer'. | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | METHOTREXATE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33388058 | 18,811,694 | 2021-01-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epstein-Barr virus associated lymphoproliferative disorder'. | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | METHOTREXATE SODIUM, PREDNISOLONE | DrugsGivenReaction | CC BY | 33388058 | 18,737,105 | 2021-01-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Peritonitis'. | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | METHOTREXATE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33388058 | 18,811,694 | 2021-01-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Small intestinal perforation'. | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | METHOTREXATE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33388058 | 18,811,694 | 2021-01-02 |
What was the administration route of drug 'PREDNISOLONE'? | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33388058 | 18,811,694 | 2021-01-02 |
What was the dosage of drug 'METHOTREXATE'? | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
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Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | 6 mg (milligrams). | DrugDosage | CC BY | 33388058 | 18,811,694 | 2021-01-02 |
What was the outcome of reaction 'Diffuse large B-cell lymphoma'? | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33388058 | 18,775,470 | 2021-01-02 |
What was the outcome of reaction 'Epstein Barr virus positive mucocutaneous ulcer'? | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33388058 | 18,811,694 | 2021-01-02 |
What was the outcome of reaction 'Epstein-Barr virus associated lymphoproliferative disorder'? | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33388058 | 18,737,105 | 2021-01-02 |
What was the outcome of reaction 'Jejunal perforation'? | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33388058 | 18,775,470 | 2021-01-02 |
What was the outcome of reaction 'Lymphoproliferative disorder'? | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33388058 | 18,811,694 | 2021-01-02 |
What was the outcome of reaction 'Peritonitis'? | Cessation of methotrexate and a small intestinal resection provide a good clinical course for a patient with a jejunum perforation induced by a methotrexate-associated lymphoproliferative disorder: a case report.
BACKGROUND
Methotrexate (MTX) is a frequently used drug in the treatment of rheumatoid arthritis (RA), but occurrences of lymphoproliferative disorders (LPD) have been reported in patients undergoing an MTX regimen. Almost half of the patients with methotrexate-associated lymphoproliferative disorders (MTX-LPD) have extranodal lesions; moreover, although extremely rare, digestive tract perforations resulting from the extranodal lesions of MTX-LPD have also been reported.
METHODS
We describe the case of an 81-year-old woman with RA who had been prescribed MTX at 6 mg per week for the past 11 years. She was admitted to our hospital with occasional abdominal pain and was first diagnosed with enteritis. Her abdominal pain did not improve, and a computed tomography scan showed abdominal effusion and free air in the abdominal cavity. She was diagnosed with a digestive tract perforation and underwent emergency surgery. The perforation site was identified in the jejunum, and she underwent small intestinal resection around the perforated region. The pathological findings showed an ulcer in the jejunum and infiltration of large atypical lymphocytes around the perforated region. An immunohistochemical examination revealed the expression of a cluster of differentiation 20 and latent membrane protein 1. Considering the patient's history of RA treated with MTX, she was diagnosed as having Epstein-Barr virus (EBV)-related MTX-LPD with a histological diagnosis of EBVMCU. MTX was discontinued after the surgery, and her soluble interleukin-2 receptor (sIL-2R) levels had returned to normal 1 year later. She has had a good course for the 2 years since surgery and remains asymptomatic with no recurrence of MTX-LPD, as confirmed by the sIL-2R levels.
CONCLUSIONS
We experienced a rare case of the jejunum perforation induced by MTX-LPD. Since only a few cases have been reported of a patient with small intestinal perforation induced by MTX-LPD, further research is necessary to evaluate the clinicopathological features of MTX-LPD. The patient had disease remission after surgery and by discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, could have a higher likelihood of remission, which could have been a factor in the present case.
Background
Methotrexate (MTX) is a key drug in the treatment of rheumatoid arthritis (RA), and one of the adverse effects can be lymphoproliferative disorders (LPD). However, the incidence of methotrexate-associated lymphoproliferative disorders (MTX-LPD) is extremely rare, reported as 0.00168/person-year [1]. MTX-LPD was categorized with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPD) in the revised 2017 fourth edition of the World Health Organization’s (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues [2]. Almost half of the patients with MTX-LPD had extranodal lesions associated with the brain, lungs, kidneys, liver, and bone marrow [3]. Extranodal lesions in the digestive tract are rare, but a few cases of patients with small intestinal perforations resulting from extranodal lesions of MTX-LPD are reported [4]. Although chemotherapy should be administered to patients who have progressive LPD, spontaneous LPD regression after MTX cessation without chemotherapy is often achieved in up to half the cases of MTX-LPD after ending MTX treatment [5]. Here, we describe a rare case of a patient with a jejunum perforation induced by MTX-LPD who underwent a partial small-intestine resection and had a remission after cessation of MTX.
Case presentation
An 81-year-old woman was admitted to our hospital due to occasional abdominal pain. She had a medical history of RA for the previous 14 years, hypertension, and nonalcoholic fatty liver disease. To control her RA, she had been taking MTX (6 mg per week) and prednisolone (5 mg/2.5 mg every other day) for the past 11 years. A physical examination revealed pain throughout her abdomen with rebound tenderness on the left side; however, she had no fever, and her abdomen was soft and flat.
Laboratory findings included a white blood cell count, 4400/μL (reference range, 3300–8600/μL); lymphocyte count, 572/μL (13%) (reference range, 18–50%); hemoglobin, 12.8 g/dL (reference range, 11.6–14.8 g/dL); platelet count, 240,000/μL (reference range, 158,000–348,000/μL); albumin, 3.6 g/dL (reference range, 4.1–5.1 g/dL); lactate dehydrogenase, 296 U/L (reference range, 124–222 U/L); and C-reactive protein, 1.91 mg/dL (reference range, 0.00–0.14 mg/dL). An abdominal computed tomography (CT) scan showed small-intestine edema, and her initial diagnosis was enteritis.
Antibiotic therapy was administered on the second day of her hospital stay because her white blood cell count increased from 4400 to 23,000/μL and her temperature increased from 35.9 to 38.5 °C. The patient’s abdominal pain also failed to improve. On the third day, the CT scan showed abdominal effusion and free air in the abdominal cavity (Fig. 1); she was diagnosed with a digestive tract perforation and peritonitis, and emergency surgery was performed. Intraoperatively, the perforation site was identified in the jejunum (about 30 cm anal-side to the Treitz ligament); the patient underwent a partial resection of the small intestine, and intraperitoneal irrigation was performed (Fig. 2).
Fig. 1 Representative images of CT scan on hospital day 3. a Perforation site (arrow) of the small intestine and abdominal effusion. b Free air in the abdomen. CT computed tomography
Fig. 2 Intraoperative findings revealed that the perforation site (arrow) was in the jejunum, about 30 cm anal-side to the Treitz ligament
The pathology of the jejunum showed a 35 mm × 4 mm ulcer and a 1-mm pinhole-shaped perforation site; infiltration of large atypical lymphocytes with small lymphocytes was observed around the perforated region (Fig. 3a–c). The immunohistochemical examination showed the expression of clusters of differentiation (CD) CD20, CD30, CD79a, and latent membrane protein 1 (LMP1) (Fig. 3d–f) and the absence of CD3, CD5, CD10, cyclinD1, cytokeratin AE1/AE3, or epithelial membrane antigen. LMP1 is a membrane protein produced by the Epstein–Barr virus (EBV), which is expressed in multiple EBV-related malignancies, including lymphomas [6, 7]. Therefore, these atypical lymphocytes were associated with diffuse large B cell lymphoma (DLBCL), a polymorphous type with Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU).
Fig. 3 a Macroscopically, a 35 mm × 4 mm ulcer with a 1-mm perforation site in the jejunum. b Surgical specimens with perforated lesions from the ulcerated jejunum (hematoxylin and eosin staining, original magnification × 12.5). c Infiltration of large atypical lymphocytes around the perforated region (hematoxylin and eosin × 600). d Immunohistochemical staining of CD20. e Immunohistochemical staining of CD30. f Immunohistochemical staining of LMP-1 (c–f original magnification × 600). CD cluster of differentiation, LMP-1 latent membrane protein 1
Due to the patient’s pathological findings and history of RA treated with MTX, she was diagnosed as having Oii-LPD, specifically MTX-LPD, with a histological diagnosis of EBVMCU. MTX was no longer prescribed for the patient, but oral medication was resumed on day 12, which included prednisolone (5 mg/2.5 mg every other day). The patient was discharged from the hospital on day 21, and positron emission tomography–computed tomography (PET–CT) was performed to evaluate the extent of the lymphoma, and it showed no findings associated with extranodal LPD.
One month after the patient had concluded her MTX treatment, her soluble interleukin-2 receptor (sIL-2R) levels had decreased from 1460 to 730 IU/mL, and it was not necessary to initiate chemotherapy. One year later, her sIL-2R level was < 520 IU/mL. The patient has continued to have a good course for 2 years after her hospitalization: she has remained asymptomatic, and her sIL-2R levels show no recurrence of MTX-LPD (Fig. 4). Her RA is controlled by bucillamine (200 mg per day) and iguratimod (25 mg per day).
Fig. 4 A flow chart of the clinical course for methotrexate-associated lymphoproliferative disorders
Discussion and conclusions
The causes for the perforation of the small intestine can be immune-mediated, infectious- or medication-related, congenital, metabolic, vascular, or neoplastic. Medication-related causes include non-steroidal anti-inflammatory drugs; enteric-coated potassium chloride; chemotherapeutic agents, such as gefitinib and erlotinib and drug combinations containing etoposide and cisplatin; and monoclonal antibodies, such as bevacizumab, IL-2, ipilimumab, and rituximab [8, 9]. Monoclonal antibody therapeutics have been approved for several cancer and inflammatory diseases. Bevacizumab has been used in the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and other malignancies, including ovarian cancer, through the inhibition of vascular endothelial growth factor [9]. IL-2 has been used in patients with metastatic melanoma and renal cell carcinoma [8]. Ipilimumab is an antibody to cytotoxic T lymphocyte-associated antigen 4 that has been used in the treatment of metastatic melanoma and renal cell cancer [9]. Rituximab, an anti-CD20 monoclonal antibody, has been used to treat hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis [9, 10]. Several side effects associated with the use of these monoclonal antibodies have been reported, with gastrointestinal perforations reported as the rare and common adverse effects [9–12] (Table 1). Malignant neoplasms (lymphomas, enteropathy-associated T cell lymphomas, adenocarcinomas, and carcinoid tumors) can also be a causative factor of small-intestine perforation [8]. One study showed that 92 of 1062 (9%) patients with lymphoma involving the gastrointestinal tract developed a perforation [13], with large B cell lymphomas being the most common type.
Table 1 Indications and side effects of using monoclonal antibodies
Monoclonal antibody Bevacizumab Interleukin-2 Ipilimumab Rituximab
Target Vascular endothelial growth factor Interleukin-2 receptor Cytotoxic T lymphocyte antigen 4 CD20 antigen
Indications Colorectal cancer, non-small cell lung cancer, and ovarian cancer Melanoma and renal cell cancer Melanoma and renal cell cancer Hematologic B cell malignancies, nephrotic syndrome, and rheumatoid arthritis
Side effects Hypertension, proteinuria, arterial thromboembolic events, wound healing complications, bleeding diathesis, and gastrointestinal perforations Fever and chills, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, a capillary leak syndrome, and intestinal perforation Dermatitis, endocrinopathies, particularly hypophysitis, uveitis, nephritis, inflammatory myopathies, hepatitis, colitis, and intestinal perforation Fever and chills, mucocutaneous reactions, fatal infusion reactions, progressive multifocal leukoencephalopathy, and intestinal perforation
CD20 cluster of differentiation 20
Patients who have a therapy regimen that includes MTX can develop MTX-LPD, which can present as a benign lymphoid proliferation or malignant lymphoma. MTX-LPD is categorized as Oii-LPD by the WHO; this is a group of disorders defined as lymphoid proliferations or lymphomas that develop in patients receiving immunosuppressive drugs for autoimmune diseases or conditions other than in the post-transplant setting [14]. Extranodal lesions have been found in the digestive tracts of 4.1% of affected patients, and 1.4% had small intestinal lesions [15]. Small-intestine perforations due to MTX-LPD can occur but are extremely rare, with 7 cases reported in the Japanese literature and a single case reported in the English literature [4, 16] (Table 2). All cases were diagnosed as DLBCL, and association with EBV was observed in 5 cases. Spontaneous regression was achieved in 6 cases, and 7 cases have been reported to survive. However, a survival of > 2 years was not reported in all cases. Considering the effect of MTX discontinuation on RA progression, we should follow up cautiously.
Table 2 Reported cases in Japan of perforation in the gastrointestinal tract caused by MTX-associated lymphoproliferative disorder
Case Year Age Sex Organ CD20 EBV Diagnosis Operation Chemotherapy Prognosis
1 1995 73 M Ileum Positive Negative DLBCL Rt. hemicolectomy No Dead
2 2004 87 F Ileum Positive − DLBCL Partial resection No Alive
3 2006 63 M Ileum Positive Positive DLBCL Ileo-cecum resection No Alive
4 2011 82 F Ileum Positive Positive DLBCL Ileo-cecum resection Yesa Alive
5 2016 70 F Ileum Positive Positive DLBCL Rt. hemicolectomy No Alive
6 2017 77 F Ileum Positive Negative DLBCL Partial resection No Alive
7 2018 66 F Ileum Positive Positive DLBCL Partial resection No Alive
8 2020 62 M Jejunum Positive Positive DLBCL Partial resection No Alive
Present case 2020 81 F Jejunum Positive Positive EBVMCU Partial resection No Alive
CD20 cluster of differentiation 20, EBV Epstein–Barr virus, DLBCL diffuse large B cell lymphoma, EBVMCU Epstein–Barr virus-positive mucocutaneous ulcer, Rt. hemicolectomy right hemicolectomy
aR-THP-COP 5course: rituximab (R), tetrahydropyranyl adriamycin (THP), cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL)
The occurrence of MTX-LPD correlates with the total dose and duration of MTX administration: the median interval between initiation of MTX treatment and the development of LPD was 30–54 months, and the median cumulative dose of MTX was 940–1500 mg [17, 18]. However, another study showed that the total dose and length of MTX administration were not associated with overall survival in patients with MTX-LPD [19]. In 18–45% of cases, spontaneous recovery from MTX-LPD takes place after MTX is discontinued [3, 19], often within 2–3 months [20]. If the LPD progresses after MTX is discontinued or high sIL-2R levels persist, chemotherapy should be administered [20]. Our case achieved a disease regression without chemotherapy, although her cumulative dose (3240 mg) and duration of MTX therapy (135 months) had been much greater than the median reported in previous studies [17, 18].
Large B cell lymphoma, including DLBCL, is the major histological subtype of MTX-LPD. Other frequent subtypes are reactive lymphoid hyperplasia, classic Hodgkin lymphoma, polymorphic B cell LPD, and indolent lymphoma which includes follicular lymphoma [21]. Some studies have shown that patients who are EBV-positive and non-DLBCL histological type have a high prevalence of spontaneous remission [22]. EBV-positive DLBCL is categorized as polymorphous lymphoma and large cell lymphoma subtypes, and a number of previous reports have revealed that the polymorphous lymphoma has a good prognosis than large cell lymphoma [23]. Additionally, some patients with EBV-positive LPD exhibited mucosal or cutaneous ulcers with polymorphous infiltration of small lymphocytes, immunoblasts, and atypical large lymphocytes, which are categorized as EBVMCU. EBVMCU is typically located in the oropharynx, gastrointestinal tract, and skin [24]. Recent studies have reported that EBVMCU develops as Oii-LPD induced by MTX treatment, and nearly all EBVMCU cases showed a favorable response to conservative management approaches such as the cessation of the MTX treatment for RA [25]. Although the detection rate of EBV is 5–10% in canonical LPD, the rate increases to 27% and 30–60% in patients with MTX-LPD and rheumatoid arthritis-associated LPD, respectively [18, 22]. Among RA patients with EBV-positive MTX-LPD, a lower incidence of DNA methylation in tumors and higher expression of tumor suppressor genes were observed. Although this may explain a higher probability of spontaneous LPD regression after MTX cessation in RA patients, the causal relationship between EBV and MTX-LPD is still unclear [22]. Another study reported that the tumor microenvironment with upregulation of autophagosome may support the development of EBV-related LPD [26]. Our case had disease regression after she concluded MTX and underwent surgery for perforated jejunum. Because she had a spontaneous recovery from MTX-LPD, chemotherapy was not required; we consider that EBV-positivity played a role in the patient’s spontaneous recovery.
In conclusion, we saw a rare case of jejunum perforation induced by EBV-related MTX-LPD. Since only a few similar cases have been reported, further research is necessary to evaluate the clinicopathological features. This case study shows that successful disease management and remission can be achieved by surgery and discontinuing MTX treatment; our case did not require chemotherapy. EBV-positive patients, especially those with a pathological presentation of EBVMCU, have a higher likelihood of remission, which may have influenced the successful outcome of the present case.
Abbreviations
MTXMethotrexate
RARheumatoid arthritis
LPDLymphoproliferative disorders
MTX-LPDMethotrexate-associated lymphoproliferative disorders
Oii-LPDOther iatrogenic immunodeficiency-associated lymphoproliferative disorders
WHOThe World Health Organization
CTComputed tomography
CDCluster of differentiation
LMP-1Latent membrane protein 1
EBVEpstein–Barr virus
DLBCLDiffuse large B cell lymphoma
EBVMCUEpstein–Barr virus-positive mucocutaneous ulcer
PET–CTPositron emission tomography–computed tomography
sIL-2RSoluble interleukin-2 receptor
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
This work was supported in part by Grants-in-Aid for Research from the National Center for Global Health and Medicine (20A 3001).
Authors’ contributions
MN and RS wrote the paper; HO, TN, KK, AS, DE, and NA contributed to the paper design and coordination. All authors have read and approved the manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Written consent was obtained from the patient. As this is a case report, approval from the institutional review board was not needed.
Consent for publication
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33388058 | 18,811,694 | 2021-01-02 |
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